Substituted 4-arylmethylene-2-imino-2,3-dihydrothiazoles and derivatives and their pharmaceutical use

ABSTRACT

Compounds of Formula I                    
     including pharmaceutically acceptable salts thereof in the form of individual enantiomers, racemates, or other mixtures of enantiomers, in which 
     Ar is phenyl, naphthyl or benzo[b]thiophenyl, each of which may be optionally substituted; R 1  and R 2 , which may be the same or different, independently are a) H, b) an alkyl group containing 1 to 6 carbon atoms, c) an alkenyl group containing 3 to 6 carbon atoms, d) a cycloalkyl group containing 3 to 7 carbon atoms, e) a cycloalkylmethyl group in which the ring contains 3 to 7 carbon atoms, f) an aryl or heteroaryl group optionally substituted g) an arylalkyl or heteroarylalkyl group each optionally substituted; or R 1  and R 2  form an alkylene chain optionally substituted by one or more alkyl groups each containing 1 to 3 carbon atoms, such that, together with the atoms to which they are attached, they form a 5 or 6 membered ring; R 3  is a) H, b) an aryl or heteroaryl group each optionally substituted c) an optionally substituted arylmethyl group; or d) an alkoxyalkyl group containing 3 to 6 carbon atoms; and R 4  and R 5 , which may be the same or different, independently are an alkyl group containing 1 to 3 carbon atoms, or R 4  and R 5  together with the atom to which they are attached form a cycloalkyl ring containing 3 to 6 carbon atoms; processes to prepare such compounds; compositions containing such compounds and their use in the treatment of depression, anxiety, Parkinson&#39;s disease, obesity, cognitive disorders, seizures, neurological disorders and as neuroprotective agents; are described.

The present invention relates to certain substituted4-arylmethylene-2-imino-2,3-dihydrothiazoles which inhibit neuronalreuptake of 5-hydroxytryptamine and/or noradrenaline and/or dopamine, toprocesses for their preparation, to pharmaceutical compositionscontaining them and to their use in the treatment of depression,anxiety, Parkinson's disease, obesity, cognitive disorders, seizures,neurological disorders such as epilepsy, and as neuroprotective agentsto protect against conditions such as stroke. The invention includesnovel arylalkyl- and arylcycloalkyldihydroimidazo[2,1 -b]thiazole,arylalkyl- and arylcycloalkyldihydro-5H-thiazolo[3,2-a]pyrimidine andarylalkyl- and arylcycloalkyldihydrothiazole compounds.

Sharpe C. J and Shadbolt R. S. disclose certaindihydroimidazo[2,1-b]thiazole compounds having antidepressant activity,Journal of Medicinal Chemistry, 1971, Vol 14 No.10, p977-982. However,the document also states that these compounds were generally less activeand more toxic than the imidazolines also disclosed in the document. Thecompounds of the present invention are not disclosed or suggested inthis document.

PCT/EP96/02676 discloses substitutedbenzo[b]thiophen-3-yldihydro-imidazo[2,1-b]thiazole,benzo[b]thiophen-3-yldihydro-5H-thiazolo[3,2-a]pyrimidine,benzo[b]furan-3-yldihydroimidazo[2,1-b]thiazole andbenzo[b]furan-3-yldihydro-5H-thiazolo[3,2-a]pyrimidine compounds whichhave affinity for 5-HT_(1A) receptors and which inhibit neuronalreuptake of 5-hydroxytryptamine and/or noradrenaline. These compoundsare stated to be useful in the treatment of CNS disorders. The compoundsof the present invention are not disclosed or suggested in thisdocument.

EP683,160 discloses inter alia iminothiazoline compounds of Formula A

in which inter alia

R₁ is C₁-C₆ (halo)alkyl, R₂ is C₁-C₆ (halo)alkyl, C₇-C₁₇ aralkyl whichmay be substituted with one or more C₁-C₃ (halo)alkyl groups, C₁-C₃(halo)alkoxy groups or halogen atoms, aryl which may be substituted; R₃is hydrogen, C₁-C₆ (halo)alkyl or a group of the general formula: CO₂R₆;X is hydrogen, chlorine or fluorine; Y is chlorine, fluorine, bromine,nitro or cyano; R₆ is hydrogen or C₁-C₃ (halo)alkyl; B is nitro, or agroup of the general formula: SR₄, or OR₄; R₄ is C₁-C₆ (halo)alkyl,C₃-C₆ (halo)alkenyl; wherein the term “(halo)” as used in the names ofthe above substituents means that they may be substituted with one ormore halogen atoms; which are herbicides.

EP600,489 discloses a process for preparing compounds of Formula B

wherein R¹ is optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl or optionally substitutedheteroaryl; R² is hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, and R³, R⁴ and R⁵are the same or different, each of which is hydrogen, optionallysubstituted alkyl or optionally substituted aryl.

U.S. Pat. No. 4,347,248 discloses2,3-disubstitutedthiazolo[3,2-a][1,3]diazacyclenes of Formula C

wherein R₁ is hydrogen, fluoro, chloro, bromo, alkyl having up to 3carbon atoms or dimethylamino; R₂ is hydrogen, fluoro, chloro, bromo oralkyl having up to 3 carbon atoms; n is zero, one or two; and Q is adivalent moiety of the formula; —CH₂—, —C(CH₃)₂——CH₂CH₂— or —CH₂CH₂CH₂—;which are diuretics.

U.S. Pat. No. 4,325,955 discloses3-benzhydrylthiazolo[3,2-a][1,3]diazacyclenes which are diuretics.

Certain cyclic 2-iminothiazoles are disclosed in J.Chem.Soc. 1995,2943-2948 and J.Chem.Soc. Perkin Trans. 1, 1989, 643-648.

The present invention provides compounds of Formula I

including pharmaceutically acceptable salts thereof in the form ofindividual enantiomers, racemates, or other mixtures of enantiomers,

in which:

Ar is phenyl, naphthyl or benzo[b]thiophenyl, each of which may beoptionally substituted by one or more substituents selected from a)halo, b) an alkyl group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, c) an alkoxy group containing 1 to 3carbon atoms optionally substituted by one or more halo, d) an alkylthiogroup containing 1 to 3 carbon atoms optionally substituted by one ormore halo, e) a phenoxy group optionally substituted by one or more haloor f) phenyl optionally substituted by one or more halo;

R₁ and R₂, which may be the same or different, independently are a) H,b) an alkyl group containing 1 to 6 carbon atoms, c) an alkenyl groupcontaining 3 to 6 carbon atoms, d) a cycloalkyl group containing 3 to 7carbon atoms, e) a cycloalkylmethyl group in which the ring contains 3to 7 carbon atoms, f) an aryl or heteroaryl group optionally substitutedby one or more substituents selected from i) halo, ii) an alkyl groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, iii) an alkoxy group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, iv) an alkylthio group containing 1 to3 carbon atoms optionally substituted by one or more halo, g) anarylalkyl or heteroarylalkyl group in which the alkyl chain contains 1to 3 carbon atoms and in which the aryl or heteroaryl group mayoptionally be substituted by one or more substituents selected from i)halo, ii) an alkyl group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, iii) an alkoxy group containing 1 to 3carbon atoms optionally substituted by one or more halo, iv) analkylthio group containing 1 to 3 carbon atoms optionally substituted byone or more halo; or R₁ and R₂ form an alkylene chain optionallysubstituted by one or more alkyl groups each containing 1 to 3 carbonatoms, such that, together with the atoms to which they are attached,they form a 5 or 6 membered ring,

R₃ is a) H, b) an aryl or heteroaryl group optionally substituted by oneor more substituents selected from i) halo, ii) an alkyl groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, iii) an alkoxy group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, iv) an alkylthio group containing 1 to3 carbon atoms optionally substituted by one or more halo, c) anarylmethyl group in which the aryl is optionally substituted by one ormore substituents selected from i) halo, ii) an alkyl group containing 1to 3 carbon atoms optionally substituted by one or more halo, iii) analkoxy group containing 1 to 3 carbon atoms optionally substituted byone or more halo, iv) an alkylthio group containing 1 to 3 carbon atomsoptionally substituted by one or more halo; or d) an alkoxyalkyl groupcontaining 3 to 6 carbon atoms; and

R₄ and R₅, which may be the same or different, independently are analkyl group containing 1 to 3 carbon atoms, or R₄ and R₅ together withthe atom to which they are attached form a cycloalkyl ring containing 3to 6 carbon atoms.

It will be understood that the term halo, when used herein, includesfluoro, chloro, bromo and iodo. It will be understood that in alkylgroups, alkylthio groups and alkoxy groups containing more than twocarbon atoms the alkyl group may be straight or branched.

The term aryl as used herein means phenyl or naphthyl preferably phenyl.The term heteroaryl as used herein means aryl in which one or more ofthe ring carbon atoms is replaced by a heteroatom such as N, S or O andfuryl and thienyl. Preferably heteroaryl means furyl, pyridyl orthienyl.

In preferred compounds of Formula I, Ar is naphthyl, benzo[b]thiophenylor phenyl optionally substituted by one or more substituents selectedfrom halo, an alkylthio group containing 1 to 3 carbon atoms, or aphenoxy group. In more preferred compounds, Ar is naphthyl,benzo[b]thiophenyl or phenyl optionally substituted by one or moresubstituents selected from chloro, bromo, methylthio, or phenoxy. Mostpreferably, Ar is 2-naphthyl, benzo[b]thiophen-2-yl, 4-chlorophenyl,3,4-dichlorophenyl, 4-bromophenyl or 4-methylthiophenyl.

In preferred compounds of Formula I, R₁ and R₂, which may be the same ordifferent, independently are a) H, b) an alkyl group containing 1 to 4carbon atoms, c) an alkenyl group containing 3 or 4 carbon atoms, d) acycloalkyl group containing 3 to 5 carbon atoms, e) a cycloalkylmethylgroup in which the ring contains 3 to 5 carbon atoms, f) an aryl orheteroaryl group optionally substituted by one or more substituentsselected from i) halo, ii) an alkyl group containing 1 to 3 carbon atomsoptionally substituted by one or more halo, iii) an alkoxy groupcontaining 1 to 3 carbon atoms, g) an arylalkyl or heteroarylalkyl groupin which the alkyl chain contains 1 or 2 carbon atoms and in which thearyl or heteroaryl group may optionally be substituted by one or moresubstituents selected from halo or an alkoxy group containing 1 to 3carbon atoms; or R₁ and R₂ form an alkylene chain such that, togetherwith the atoms to which they are attached, they form a 5 or 6 memberedring, optionally substituted by one or more methyl groups.

In more preferred compounds, R₁ and R₂ are a) an alkyl group containing1 to 4 carbon atoms, b) allyl, c) cyclopentyl, d) cyclopropylmethyl, e)an aryl group optionally substituted by one or more substituentsselected from i) halo, ii) methyl, iii) trifluoromethyl, iv) ethoxy, f)an arylalkyl or heteroarylalkyl group in which the alkyl chain contains1 or 2 carbon atoms and in which the aryl or heteroaryl group mayoptionally be substituted by one or more substituents selected from haloor methoxy; or R₁ and R₂ form an alkylene chain such that, together withthe atoms to which they are attached, they form a 5 or 6 membered ring,optionally substituted by one or more methyl groups.

Most preferably, R₁ and R₂ are methyl, ethyl, propyl, isopropyl, butyl,isobutyl, allyl, cyclopropylmethyl, benzyl, 4-fluorobenzyl,pyrid-3-ylmethyl, furfuryl, phenethyl or 2-(3,4-dimethoxyphenyl)ethyl;or R₁ and R₂ form an alkylene chain such that, together with the atomsto which they are attached, they form a 5 or 6 membered ring, optionallysubstituted by a methyl group.

In one group of especially preferred compounds of Formula I, R₁ and R₂are identical and satisfy any of the above definitions. In another groupof especially preferred compounds of Formula I, R₁ and R₂ form analkylene chain such that, together with the atoms to which they areattached, they form a 5 or 6 membered ring, optionally substituted by amethyl group.

In preferred compounds of Formula I, R₃ is H, an aryl or heteroarylgroup optionally substituted by one or more halo, an arylmethyl group inwhich the aryl is optionally substituted by one or more halo, or analkoxyalkyl group containing 3 to 6 carbon atoms. In more preferredcompounds R₃ is H, phenyl, 4-chlorophenyl, benzyl or 2-methoxyethyl.Most preferably, R₃ is H.

In preferred compounds of Formula I, R₄ and R₅, which may be the same ordifferent, independently are methyl, or R₄ and R₅ together with the atomto which they are attached form a cycloalkyl ring containing 3 to 6carbon atoms. Most preferably R₄ and R₅ are methyl, or R₄ and R₅together with the atom to which they are attached form a cyclobutane,cyclopentane or cyclohexane ring.

A preferred group of compounds of Formula I is represented by Formula Ia

including pharmaceutically acceptable salts thereof in the form ofindividual enantiomers, racemates, or other mixtures of enantiomers,

in which

m is 2, 3 or 4;

n is 2 or 3;

Ar is phenyl or naphthyl, each of which may be optionally substituted byone or more substituents selected from a) halo, b) an alkyl groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, c) an alkoxy group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, d) an alkylthio group containing 1 to 3carbon atoms optionally substituted by one or more halo, or e) phenyl;and

R_(a) and R_(b) independently are H or an alkyl group containing 1 to 3carbon atoms optionally substituted by one or more halo; and

R₃ is H.

In preferred compounds of Formula Ia, m is 3.

In preferred compounds of Formula Ia, n is 2.

In preferred compounds of Formula Ia, Ar is naphthyl, or phenylsubstituted by one or two halo substituents. More preferably Ar isnaphthyl, or phenyl substituted by one or two chloro substituents. Mostpreferably, Ar is 2-naphthyl or 4-chlorophenyl or 3,4-dichlorophenyl.

In preferred compounds of Formula Ia, R_(a), R_(b) and R₃ are each H.

In one group of preferred compounds of Formula Ia, m is 3; n is 2 or 3;Ar is phenyl or naphthyl, each of which may be optionally substituted byone or more substituents selected from a) halo, b) an alkyl groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, c) an alkoxy group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, d) an alkylthio group containing 1 to 3carbon atoms optionally substituted by one or more halo, or e) phenyl;R_(a) and R_(b) independently are H or an alkyl group containing 1 to 3carbon atoms optionally substituted by one or more halo and R₃ is H.Preferably, R_(a), R_(b) and R₃ are each H.

In a further group of preferred compounds of Formula Ia, m is 3; n is 2;Ar is phenyl or naphthyl, each of which may be optionally substituted byone or more substituents selected from a) halo, b) an alkyl groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, c) an alkoxy group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, d) an alkylthio group containing 1 to 3carbon atoms optionally substituted by one or more halo, or e) phenyl;and R_(a) and R_(b) independently are H or an alkyl group containing 1to 3 carbon atoms optionally substituted by one or more halo and R₃ isH. Preferably, R_(a), R_(b) and R₃ are each H.

Compounds of Formula I may exist as salts with pharmaceuticallyacceptable acids. The present invention includes all such salts.Examples of such salts include hydrochlorides, hydrobromides, sulphates,methanesulphonates, nitrates, maleates, acetates, citrates, fumarates,tartrates [eg (+)-tartrates, (−)-tartrates or mixtures thereof includingracemic mixtures], succinates, benzoates and salts with amino acids suchas glutamic acid.

Certain compounds of Formula I may exist in different tautomeric formsor as different geometric isomers, and the present invention includeseach tautomer and/or geometric isomer of compounds of Formula I andmixtures thereof.

Certain compounds of Formula I may exist in different stableconformational forms which may be separable. For example, if R₃ is abulky group there may be restricted rotation about one or more singlebond or bonds due to steric hindrance. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The present invention includes each conformational isomer ofcompounds of Formula I and mixtures thereof.

Certain compounds of Formula I and their salts may exist in more thanone crystal form and the present invention includes each crystal formand mixtures thereof. Certain compounds of Formula I and their salts mayalso exist in the form of solvates, for example hydrates, and thepresent invention includes each solvate and mixtures thereof.

Certain compounds of Formula I contain one or more chiral centres, andexist in different optically active forms. When compounds of Formula Icontain one chiral centre, the compounds exist in two enantiomeric formsand the present invention includes both enantiomers and mixtures ofenantiomers. The enantiomers may be resolved by methods known to thoseskilled in the art, for example by formation of diastereoisomeric saltswhich may be separated, for example, by crystallisation; formation ofdiastereoisomeric derivatives or complexes which may be separated, forexample, by crystallisation, gas-liquid or liquid chromatography; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. It will be appreciated that where thedesired enantiomer is converted into another chemical entity by one ofthe separation procedures described above, a further step is required toliberate the desired enantiomeric form. Alternatively, specificenantiomers may be synthesised by asymmetric synthesis using opticallyactive reagents, substrates, catalysts or solvents, or by converting oneenantiomer into the other by asymmetric transformation.

When a compound of Formula I contains more than one chiral centre it mayexist in diastereoisomeric forms. The diastereoisomeric pairs may beseparated by methods known to those skilled in the art, for examplechromatography or crystallisation and the individual enantiomers withineach pair may be separated as described above. The present inventionincludes each diastereoisomer of compounds of Formula I and mixturesthereof.

Specific compounds of Formula I are

3-[1-(3,4-Dichlorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(4-Chlorophenyl)cyclobutyl]-6,7-dihydro-5H-thiazolo[3,2-a]pynimidine;

3-[1-(4-Chlorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(3,4-Dichlorophenyl)cyclobutyl]-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine;

3-[1-(2-Naphthyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(3,4-Dichlorophenyl)cyclopentyl]-5,6-dihydroimidazo[2,1-b]thiazole;

2-Benzyl-3-[1-(4-chlorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(3,4-Dichlorophenyl)cyclobutyl]-2-(2-methoxyethyl)-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(3,4-Dichlorophenyl)cyclobutyl]-2-phenyl-5,6-dihydroimidazo[2,1-b]thiazole;

2-(4-Chlorophenyl)-3-[1-(3,4-dichlorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(3,4-Dichlorophenyl)-1-methylethyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(Benzo[b]thiophen-2-yl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(3,4-Dichlorophenyl)cyclobutyl]-5-methyl-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(3,4-Dichlorophenyl)cyclobutyl]-6-methyl-5,6-dihydroimidazo[2,1-b]thiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-methyl-2-methylimino-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-ethyl-2-ethylimino-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-propyl-2-propylimino-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-isopropyl-2-isopropylimino-2,3-dihydrothiazole;

3-Butyl-2-butylimino-4-[1-(3,4-dichlorophenyl)cyclobutyl]-2,3-dihydrothiazole;

4-[1-(3,4-Dichloropheny)cyclobutyl]-3-isobutyl-2-isobutylimino-2,3-dihydrothiazole;

3-Allyl-2-allylimino-4-[1-(3,4-dichlorophenyl)cyclobutyl]-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-cyclopropylmethyl-2-cyclopropylmethylimino-2,3-dihydrothiazole;

3-Benzyl-2-benzylimino-4-[1-(3,4-dichlorophenyl)cyclobutyl]-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(4-fluorobenzyl)-2-(4-fluorobenzylimino)-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-phenethyl-2-phenethylimino-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(3-pyridylmethyl)-2-(3-pyridylmethylimino)-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-furfuryl-2-furfurylimino-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-phenyl-2-phenylimino-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(p-tolyl)-2-(p-tolylimino)-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(otolyl)-2-(o-tolylimino)-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(3-trifluoromethylphenyl)-2-(3-trifluoromethylphenylimino)-2,3-trifluoromethylphenylimino)-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(2,4-xylyl)-2-(2,4-xylylimino)-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(4-ethoxyphenyl)-2-(4-ethoxyphenylimino)-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazole;

3-[1-(2-Naphthyl)cyclobutyl]-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine;

5-Methyl-3-[1-(2-naphthyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;

6-Methyl-3-[1-(2-naphthyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-Methyl-2-methylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

3-Ethyl-2-ethylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

4-[1-(2-Naphthyl)cyclobutyl]-3-propyl-2-propylimino-2,3-dihydrothiazole;

3-Isopropyl-2-isopropylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

3-Butyl-2-butylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

3-Isobutyl-2-isobutylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

3-Allyl-2-allylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

3-Cyclopropylmethyl-2-cyclopropylmethylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

3-Benzyl-2-benzylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

3-(4-Fluorobenzyl)-2-(4-fluorobenzylimino)-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

4-[1-(2-Naphthyl)cyclobutyl]-3-phenethyl-2-phenethylimino-2,3-dihydrothiazolehydrobromide;

4-[1-(2-Naphthyl)cyclobutyl]-3-(3-pyridylmethyl)-2-(3-pyridylmethylimino)-2,3-dihydrothiazole;

3-Furfuryl-2-furfurylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

4-[1-(2-Naphthyl)cyclobutyl]-3-phenyl-2-phenylimino-2,3-dihydrothiazole;

4-[1-(2-Naphthyl)cyclobutyl]-3-(p-tolyl)-2-(p-tolylimino)-2,3-dihydrothiazole;

4-[1-(2-Naphthyl)cyclobutyl]-3-(o-tolyl)-2-(o-tolylimino)-2,3-dihydrothiazole;

4-[1-(2-Naphthyl)cyclobutyl]-3-(2,4-xylyl)-2-(2,4-xylylimino)-2,3-dihydrothiazole;

3-Cyclopentyl-2-cyclopentylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

3-(4-Ethoxyphenyl)-2-(4-ethoxyphenylimino)-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

3-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;

3-Butyl-2-butylimino-4-[1-(4-chlorophenyl)cyclobutyl]-2,3-dihydrothiazole;

4-[1-(4-Bromophenyl)cyclobutyl]-3-butyl-2-butylimino-2,3-dihydrothiazole;

3-Butyl-2-butylimino-4-[1-(4-methylthiophenyl)cyclobutyl]-2,3-dihydrothiazole;

3-Butyl-2-butylimino-4-[1-(4-phenoxyphenyl)cyclobutyl]-2,3-dihydrothiazole;

3-Butyl-2-butylimino-4-[1-(4-chlorophenyl)cyclopentyl]-2,3-dihydrothiazole;

3-Butyl-2-butylimino-4-(1-phenylcyclohexyl)-2,3-dihydrothiazole;

3-Butyl-2-butylimino-4-[1-(4-chlorophenyl)-1-methylethyl]-2,3-dihydrothiazole;

3-Butyl-2-butylimino-4-[1-(3,4-dichlorophenyl)-1-methylethyl]-2,3-dihydrothiazole;

4-[1-(4-Chlorophenyl)cyclobutyl-3-phenethyl-2-phenethylimino-2,3-dihydrothiazole;

4-[1-(4-Chlorophenyl)cyclobutyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazole;

4-[1-(4-Bromophenyl)cyclobutyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazole;

4-[1-(4-Chlorophenyl)cyclopentyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazole;

3-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-4-(1-phenylcyclohexyl)-2,3-dihydrothiazole;

4-[1-(3,4-Dichlorophenyl)-1-methylethyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazole;

3-[1-(4-Bromophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(4-Chlorophenyl)cyclopentyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-(1-Phenylcyclohexyl)-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(4-Chlorophenyl)-1-methylethyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(3,4-Dichlorophenyl)-1-methylethyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(3-Fluorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;

3-[1-(4-Methylthiophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;

including pharmaceutically acceptable salts thereof and individualenantiomers, racemates or other mixtures of enantiomers.

The present invention also includes pharmaceutical compositionscomprising a therapeutically effective amount of a compound of Formula Ior a salt thereof together with a pharmaceutically acceptable diluent orcarrier.

As used hereinafter, the term “active compound” denotes a compound ofFormula I or a salt thereof. In therapeutic use, the active compound maybe administered orally, rectally, parenterally or topically, preferablyorally. Thus the therapeutic compositions of the present invention maytake the form of any of the known pharmaceutical compositions for oral,rectal, parenteral or topical administration. Pharmaceuticallyacceptable carriers suitable for use in such compositions are well knownin the art of pharmacy. The compositions of the invention may contain0.1-99% by weight of active compound. The compositions of the inventionare generally prepared in unit dosage form. Preferably the unit dosageof active ingredient is 1-500 mg. The excipients used in the preparationof these compositions are the excipients known in the pharmacists art.

Compositions for oral administration are the preferred compositions ofthe invention and these are the known pharmaceutical forms for suchadministration, for example tablets, capsules, syrups and aqueous or oilsuspensions. The excipients used in the preparation of thesecompositions are the excipients known in the pharmacist's art. Tabletsmay be prepared by mixing the active compound with an inert diluent suchas calcium phosphate in the presence of disintegrating agents, forexample maize starch, and lubricating agents, for example magnesiumstearate, and tableting the mixture by known methods. The tablets may beformulated in a manner known to those skilled in the art so as to give asustained release of the compounds of the present invention. Suchtablets may, if desired, be provided with enteric coatings by knownmethods, for example by the use of cellulose acetate phthalate.Similarly, capsules, for example hard or soft gelatin capsules,containing the active compound with or without added excipients, may beprepared by conventional means and, if desired, provided with entericcoatings in a known manner. The tablets and capsules may convenientlyeach contain 1 to 500 mg of the active compound. Other compositions fororal administration include, for example, aqueous suspensions containingthe active compound in an aqueous medium in the presence of a non-toxicsuspending agent such as sodium carboxymethylcellulose, and oilysuspensions containing a compound of the present invention in a suitablevegetable oil, for example arachis oil.

Solid oral dosage forms may be formulated in a manner known to thoseskilled in the art so as to give a sustained release of the activecompound. Enteric coated, solid oral dosage forms comprisingcompositions of the present invention may be advantageous, depending onthe nature of the active compound. Various materials, for exampleshellac and/or sugar, may be present as coatings, or to otherwise modifythe physical form of the oral dosage form. For example tablets or pillsmay, if desired, be provided with enteric coatings by known methods, forexample by the use of cellulose acetate phthalate and/or hydroxy propylmethylcellulose phthalate.

Capsules and/or caplets (for example hard or soft gelatin capsules)comprising the active compound (with or without added excipients such asa fatty oil), may be prepared by conventional means and, if desired,provided with enteric coatings in a known manner. The contents of thecapsule and/or caplet may be formulated using known methods to givesustained release of the active compound.

Liquid oral dosage forms comprising compositions of the presentinvention may be an elixir, suspension and/or syrup (for example,aqueous suspensions containing the active compound in an aqueous mediumin the presence of a non-toxic suspending agent [such as sodiumcarboxymethylcellulose] and/or oily suspensions containing the activecompound in a suitable vegetable oil [such as arachis oil and/orsunflower oil]). Liquid oral dosage forms may also comprise one or moresweetening agent, flavouring agent, preservatives and/or mixturesthereof.

The active compound may be formulated into granules with or withoutadditional excipients. The granules may be ingested directly by thepatient or they may be added to a suitable liquid carrier (for examplewater) before ingestion. The granules may contain disintegrants (forexample a pharmaceutically acceptable effervescent couple formed from anacid and a carbonate or bicarbonate salt) to facilitate dispersion inthe liquid medium.

Preferably each of the above oral dosage forms may contain from about 1mg to about 1000 mg, more preferably from about 5 mg to about 500 mg(for example 10 mg, 50 mg, 100 mg, 200 mg, or 400 mg) of the activecompound.

Compositions of the invention suitable for rectal administration are theknown pharmaceutical forms for such administration, for example,suppositories with hard fat, semi-synthetic glyceride, cocoa butterand/or polyethylene glycol bases.

Pharmaceutical compositions may also be administered parenterally (forexample subcutaneously, intramuscularly, intradermally and/orintravenously [such as by injection and/or infusion] in the knownpharmaceutical dosage forms for parenteral administration (for examplesterile suspensions in aqueous and/or oily media and/or sterilesolutions in suitable solvents, preferably isotonic with the blood ofthe intended patient). Parenteral dosage forms may be sterilised (forexample by micro-filtration and/or using suitable sterilising agents[such as ethylene oxide]). Optionally one or more of the followingpharmaceutically acceptable adjuvants suitable for parenteraladministration may be added to parenteral dosage forms: localanaesthethetics, preservatives, buffering agents and/or mixturesthereof. Parenteral dosage forms may be stored in suitable sterilesealed containers (for example ampoules and/or vials) until use. Toenhance stability during storage the parenteral dosage form may befrozen after filling the container and fluid (for example water) may beremoved under reduced pressure.

Pharmaceutical compositions may be administered nasally in knownpharmaceutical forms for such administration (for example sprays,aerosols, nebulised solutions and/or powders). Metered dose systemsknown to those skilled in the art (for example aerosols and/or inhalers)may be used.

Pharmaceutical compositions may be administered to the buccal cavity(for example sub-lingually) in known pharmaceutical forms for suchadministration (for example slow dissolving tablets, chewing gums,troches, lozenges, pastilles, gels, pastes, mouthwashes, rinses and/orpowders).

Compositions for topical administration may comprise a matrix in whichthe pharmacologically active compounds of the present invention aredispersed so that the compounds are held in contact with the skin inorder to administer the compounds transdermally. A suitable transdermalcomposition may be prepared by mixing the pharmaceutically activecompound with a topical vehicle, such as a mineral oil, petrolatumand/or a wax, for example paraffin wax or beeswax, together with apotential transdermal accelerant such as dimethyl sulphoxide orpropylene glycol. Alternatively the active compounds may be dispersed ina pharmaceutically acceptable cream or ointment base. The amount ofactive compound contained in a topical formulation should be such that atherapeutically effective amount of the compound is delivered during theperiod of time for which the topical formulation is intended to be onthe skin.

The compounds of the present invention may also be administered bycontinuous infusion either from an external source, for example byintravenous infusion or from a source of the compound placed within thebody. Internal sources include implanted reservoirs containing thecompound to be infused which is continuously released for example byosmosis and implants which may be (a) liquid such as a suspension orsolution in a pharmaceutically acceptable oil of the compound to beinfused for example in the form of a very sparingly water-solublederivative such as a dodecanoate salt or (b) solid in the form of animplanted support, for example of a synthetic resin or waxy material,for the compound to be infused. The support may be a single bodycontaining all the compound or a series of several bodies eachcontaining part of the compound to be delivered. The amount of activecompound present in an internal source should be such that atherapeutically effective amount of the compound is delivered over along period of time.

In some formulations it may be beneficial to use the compounds of thepresent invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

In the compositions of the present invention the active compound may, ifdesired, be associated with other compatible pharmacologically activeingredients.

The present invention also comprises a compound of Formula I for use asa medicament.

The pharmaceutical compositions containing a therapeutically effectiveamount of a compound of Formula I may be used to treat depression,anxiety, Parkinson's disease, obesity, cognitive disorders, seizures,neurological disorders such as epilepsy, and as neuroprotective agentsto protect against conditions such as stroke in human beings. Whilst theprecise amount of active compound administered in such treatment willdepend on a number of factors, for example the age of the patient, theseverity of the condition and the past medical history, and always lieswithin the sound discretion of the administering physician, the amountof active compound administered per day is in the range 1 to 1000 mgpreferably 5 to 500 mg given in single or divided doses at one or moretimes during the day.

In yet another aspect, the present invention provides the use of acompound of Formula I in the manufacture of a medicament for use in thetreatment of depression, anxiety, Parkinson's disease, obesity,cognitive disorders, seizures, neurological disorders such as epilepsy,and as a neuroprotective agent to protect against conditions such asstroke.

The present invention also provides a method of treating depression,anxiety, Parkinson's disease, obesity, cognitive disorders, seizures,neurological disorders such as epilepsy, and of neuroprotection toprotect against conditions such as stroke in human beings whichcomprises the administration of a therapeutically effective amount of acompound of Formula I to a patient in need thereof.

Compounds of Formula I may be administered as a method of treatingParkinson's Disease either alone or in combination with a dopamineprecursor, such as levodopa and/or a dopa decarboxylase inhibitor suchas carbidopa or benserazide, or in combination with a dopamine agonistsuch as pramipexole or in combination with catechol-O-methyltransferaseinhibitors such as tolcapone or entacapone.

Processes for the preparation of compounds of Formula I will now bedescribed. The processes may be performed on an individual basis, or bymultiple parallel synthesis, also known as High Speed Analoguing. Theprocesses are preferably carried out at atmospheric pressure.

Compounds of Formula I may be prepared by heating a compound of FormulaII

in which Ar, R₁, R₂, R₃, R₄ and R₅ are as hereinbefore defined,optionally in the presence of an acid, for example acetic acid, at atemperature in the range 0-200° C.; preferably in the range 20-150° C.

Compounds of Formula II may be prepared by reaction of a compound ofFormula III

in which R₁ and R₂ are as hereinbefore defined, with a compound ofFormula IV

in which Z is a leaving group, for example a halo such as bromo, and Ar,R₃, R₄ and R₅ are as hereinbefore defined, at a temperature in the range0-200° C., in the presence of a solvent, for example acetone; preferablyby heating at a temperature in the range 20-150° C.

Compounds of Formula I may also be prepared directly by reaction of acompound of Formula III with a compound of Formula IV at a temperaturein the range of 0-200° C., optionally in the presence of an acid, forexample acetic acid, and optionally in the presence of a solvent, forexample ethanol, without isolation of the intermediate of Formula II;preferably by heating at a temperature in the range 20-150° C.

Compounds of Formula IV in which Z is halo may be prepared by reactionof a compound of Formula V

in which Ar, R₃, R₄ and R₅ are as hereinbefore defined, with ahalogenating agent, for example bromine at a temperature in the range0-200° C. in the presence of a solvent, for example ether or methanoland dichloromethane; preferably at an initial temperature of 0-50° C.,then at a temperature in the range 20-150° C.

Compounds of Formula V may be readily prepared by methods described in,or closely analogous to those described in the patent GB2098602.

Compounds of Formula Ia may be prepared by processes analogous to thosedescribed for the preparation of compounds of Formula I.

The ability of compounds of Formula I to interact with dopamine (DA)reuptake sites has been demonstrated for the products of Examples 1 to 5by the following test which determines the ability of compounds toinhibit dopamine uptake in vitro.

Striatal tissue from the brains of male Charles River rats weighing150-250 g was homogenised in ice-cold 0.32M sucrose (1:10 w/v) using amotor driven teflon pestle (difference in diameter between mortar andpestle 0.5 mm). Nuclei and cell debris were removed by centrifugation at1,500 g at 4° C. for 10 minutes. The pellet (P1) was discarded and thesupernatant centrifuged at 28,000 g at 4° C. for 10 minutes. The crudesynaptosomal pellet (P2) was resuspended in Krebs-Henseleit buffer(equivalent to 4.2 mg wet weight of tissue/ml).

Crude synaptosomes were incubated in a shaking water bath at 37° C. for15 minutes. Aliquots (150 μl; equivalent to 0.625 mg wet weight oftissue/tube) were then added to tubes containing 275 μl ofKrebs-Henseleit buffer and 50 μl of Krebs-Henseleit buffer (totaluptake) or 50 μl of test compound (10 concentrations ranging from10⁻¹¹-10⁻⁴M or 50 μl of GBR 12909 (10⁻⁵M; non-specific uptake). Uptakewas initiated by the addition of 25 μl of freshly prepared [³H]dopamine(2.5 nM), followed by vortexing and was continued for 5 minutes at 37°C. in the shaking water bath.

Uptake was terminated by filtration under vacuum through Skatron 11735filters using a Skatron cell harvester. Filters were then washed with 8ml ice-cold saline. The scored filter paper discs were punched intovials, scintillation fluid added and radioactivity determined by liquidscintillation counting.

The ability of compounds of Formula I to interact with5-hydroxytryptamine (5-HT) reuptake sites has been demonstrated for theproducts of Examples 1 to 5 by the following test which determines theability of compounds to inhibit 5-HT uptake in vitro.

Frontal cortical tissue from the brains of male Sprague-Dawley rats(Charles River; weight range 150-250 g) was homogenised in ice-cold0.32M sucrose (1:10 w/v) using a motor driven teflon pestle (differencein diameter between mortar and pestle 0.5 mm). Nuclei and cell debriswere removed by centrifugation at 1,500 g at 4° C. for 10 minutes. Thepellet (P1) was discarded and the supernatant centrifuged at 28,000 g at4° C. for 10 minutes. The crude synaptosomal pellet (P2) was resuspendedin Krebs-Henseleit buffer (equivalent to 8.3 mg wet weight oftissue/ml).

Crude synaptosomes were incubated in a shaking water bath at 37° C. for15 minutes. Aliquots (150 μl; equivalent to 1.25 mg wet weight oftissue/tube) were then added to tubes containing 275 μl ofKrebs-Henseleit buffer and 50 μl of Krebs-Henseleit buffer (totaluptake) or 50 μl of test compound (at 10 concentrations ranging from10⁻¹¹-10⁻⁴M) or 50 μl of zimeldine (10⁻⁵M; non-specific uptake). Uptakewas initiated by the addition of 25 μl of freshly prepared [³H]5-HT (2nM), followed by vortexing, and was continued for 5 minutes at 37° C. inthe shaking water bath. Uptake was terminated by filtration under vacuumthrough Skatron 11734 filters using a Skatron cell harvester. Filterswere then washed with 8 ml ice-cold saline. The scored filter paperdiscs were punched into vials, scintillation fluid added andradioactivity determined by liquid scintillation counting.

The ability of compounds of Formula I to interact with noradrenaline(NA) reuptake sites has been demonstrated for the products of Examples 1to 5 by the following test which determines the ability of compounds toinhibit noradrenaline uptake in vitro.

Frontal cortical tissue from the brains of male Sprague-Dawley rats(Charles River; weight range 150-250 g) was homogenised in ice-cold0.32M sucrose (1:10 w/v) using a motor driven teflon pestle (differencein diameter between mortar and pestle 0.5 mm). Nuclei and cell debriswere removed by centrifugation at 1,500 g at 4° C. for 10 minutes. Thepellet (P1) was discarded and the supernatant centrifuged at 28,000 g at4° C. for 10 minutes. The crude synaptosomal pellet (P2) was resuspendedin Krebs-Physiological buffer (equivalent to 16.7 mg wet weight oftissue/ml).

Crude synaptosomes were incubated in a shaking water bath at 37° C. for15 minutes. Aliquots (150 μl; equivalent to 2.5 mg wet weight oftissue/tube) were then added to tubes containing 275 μl ofKrebs-Physiological buffer and 50 μl of Krebs-Physiological buffer(total uptake) or 50 μl of test compound (at 10 concentrations rangingfrom 10⁻-10⁻⁴M) or 50 μl of desipramine (10⁻⁵M; non-specific uptake).Uptake was initiated by the addition of 25 μl of freshly prepared[³H]noradrenaline (10 nM), followed by vortexing and was continued for 5minutes at 37° C. in the shaking water bath. Uptake was terminated byfiltration under vacuum through Whatman GF/B filters using a Brandelcell harvester. Filters were then washed with 8 ml ice-cold saline. Thescored filter paper discs were placed into vials, scintillation fluidadded and radioactivity determined by liquid scintillation counting.

For each of the dopamine (DA) uptake, 5-hydroxytryptamine (5-HT) uptakeand noradrenaline (NA) uptake inhibition tests, the percentageinhibition of specific uptake of the tritiated ligand was calculated foreach concentration of test compound. Inhibition curves were thenproduced. The concentration which gave 50% inhibition of specific uptake(IC₅₀) was obtained from the curve. The inhibition constant (K_(i)) wasthen calculated using the formula$K_{i} = \frac{{IC}_{50}}{1 + \left( {\lbrack{ligand}\rbrack/{Km}} \right)}$

in which [ligand] is the concentration of tritiated ligand used and Kmis the affinity of the uptake site for the ligand. The K_(i) values (nM)obtained in the above tests for DA, 5-HT and NA uptake inhibition foreach of the final products of Examples 1 to 5 hereinafter are given inTable 1 below. Values are means of three independent determinationsunless otherwise indicated.

TABLE 1 Example No. DA uptake 5-HT uptake NA uptake 1 9.2 nM 120 nM 34nM 2 104 nM 782 nM 261 nM 3 79 nM 795 nM 22 nM 4 9.5 nM 137 nM 15 nM 55.9 nM 25 nM 4.4 nM

The ability of compounds of Formula I to interact with dopamine (DA)reuptake sites has been demonstrated for the products of Examples 6 to76 by the following test which determines the ability of compounds todisplace the standard ligand, [³H]GBR 12935, from dopamine reuptakesites in vitro.

Striatal tissue from the brains of male Charles River rats weighing150-250 g was homogenised in ice-cold 0.32M sucrose (1:80 w/v) using amotor driven teflon pestle (12 strokes, 800 rpm) and centrifuged at 1000g for 12 minutes. The supernatant was stored on ice and the pellet wasresuspended in 0.32M sucrose (1:80 w/v) and centrifuged at 850 g for 10minutes. Combined supernatants were diluted to 1:320 w/v with ice-cold50 mM Tris-HCl, pH 7.4 (at 25° C.) containing 200 mM sodium chloride and5 mM potassium chloride (Tris buffer) and centrifuged at 40,000 g for 10minutes. The resulting pellet was resuspended in 10 ml of 50 mM Trisbuffer, incubated at 37° C. for 10 min, diluted in 50 mM Tris buffer(1:320 w/v) and recentrifuged at 40,000 g for 10 minutes. The finalpellet was resuspended in 50 mM Tris buffer (equivalent to 1.25 mg wetweight of tissue/ml) and used immediately in the binding assay. Allcentrifugations were carried out at 4° C.

Membranes (800 μl; equivalent to 1 mg wet weight of tissue/tube) wereincubated with 100 μl [³H]GBR 12935 at a single concentration of 1 nMand 100 μl of distilled water (total binding) or 100 μl of test compound(10⁻⁶M) or 100 μl of mazindol (1 μM; non-specific binding) for 90 min at4° C.

Membrane bound radioactivity was recovered by filtration under vacuumthrough Whatman GF/C filters, pre-soaked for 1 h in 0.5%polyethylenimine, using a Brandel cell harvester. Filters were rapidlywashed with 16 ml of ice-cold 50 mM Tris-HCl, pH 7.4 and radioactivitydetermined by liquid scintillation counting (2 ml Packard MV Goldscintillator).

The ability of compounds of Formula I to interact with5-hydroxytryptamine (5-HT) reuptake sites has been demonstrated for theproducts of Examples 6 to 76 by the following test which determines theability of compounds to displace the standard ligand, [³H]paroxetine,from 5-HT reuptake sites in vitro.

Frontal cortical tissue from the brains of male Charles River ratsweighing 150-250 g was homogenised in ice-cold 0.25M sucrose (1:30 w/v)using a Kinematic polytron (speed setting 6 for 30 seconds) andcentrifuged at 1000 g for 12 minutes. The supernatant was stored on iceand the pellet was resuspended in 0.25M sucrose (1:20 w/v) andcentrifuged at 850 g for 10 minutes. Combined supernatants were dilutedto 1:100 w/v with ice-cold 50 mM Tris-HCl, pH 7.5 (at 25° C.) containing120 mM sodium chloride and 5 mM potassium chloride (Tris buffer) andcentrifuged at 40,000 g for 10 minutes. The resulting pellet wasresuspended in 50 mM Tris buffer (1:100 w/v) and recentrifuged at 40,000g for 10 minutes. The final pellet was resuspended in 50 mM Tris buffer(equivalent to 2 mg wet weight of tissue/ml) and used immediately in thebinding assay. All centrifugations were carried out at 4° C.

Membranes (1000 μl; equivalent to 2 mg wet weight of tissue/tube) wereincubated with 200 μl [³H]paroxetine at a single concentration of 30 pMand 200 μl of distilled water (total binding) or 200 μl of test compound(10⁻⁶M) or 200 μl of citalopram (1 μM; non-specific binding) for 2 h at22° C.

Membrane bound radioactivity was recovered by filtration under vacuumthrough Whatman GFIC filters using a Brandel cell harvester. Filterswere rapidly washed with 16 ml ice-cold 50 mM Tris buffer andradioactivity determined by liquid scintillation counting (2 ml PackardMV Gold scintillator).

The ability of compounds of Formula I to interact with noradrenaline(NA) reuptake sites has been demonstrated for the products of Examples 6to 76 by the following test which determines the ability of compounds todisplace the standard ligand, [³H]nisoxetine, from noradrenalinereuptake sites in vitro.

Frontal cortical tissue from the brains of male Charles River ratsweighing 150-250 g was homogenised in ice-cold 50 mM Tris-HCl, pH 7.4(at 25° C.) containing 120 mM sodium chloride and 5 mM potassiumchloride (Tris buffer; 1:60 w/v) using a Kinematic polytron (speedsetting 6 for 30 seconds) and centrifuged at 40,000 g for 10 minutes.The supernatant was discarded and the pellet rehomogenised in Trisbuffer, 1:60 w/v, and centrifuged at 40,000 g for 10 minutes. This stepwas repeated twice more so that, in total, the brain tissue washomogenised and centrifuged four times. The final pellet was resuspendedin 50 mM Tris-HCl, pH 7.4 containing 300 mM sodium chloride and 5 mMpotassium chloride (equivalent to 25 mg wet weight of tissue/ml) andused immediately in the binding assay. All centrifugations wereperformed at 4° C.

Membranes (400 μl; equivalent to 10 mg wet weight of tissue/tube) wereincubated with 50 μl [³H]nisoxetine at a single concentration of 0.6 nMand 50 μl of distilled water (total binding) or 50 μl of test compound(10⁻⁶M) or 50 μl of mazindol (1 μM; non-specific binding) for 4 h at 4°C.

Membrane bound radioactivity was recovered by filtration under vacuumthrough Skatron 11734 filters using a Skatron cell harvester. Filterswere rapidly washed with ice-cold 50 mM Tris-HCl, pH 7.4 containing 120mM sodium chloride and 5 mM potassium chloride (wash setting 9,9,0) andradioactivity determined by liquid scintillation counting (1 ml PackardMV Gold scintillator).

For each of these tests measuring the ability of compounds of Formula Ito displace standard ligands from dopamine (DA), 5-hydroxytryptamine(5-HT) and noradrenaline (NA) reuptake sites in vitro, the percentagedisplacement of specific binding of tritiated ligand by 10⁻⁶M testcompound was calculated in the following way:

Firstly, specific binding of tritiated ligand in the absence (A) andpresence (B) of test compound was determined:

In the absence of compound:

A (dpm)=Total binding (dpm)-Non-specific binding (dpm)

In the presence of compound (10⁻⁶M):

B (dpm)=Binding at 10⁻⁶M (dpm)-Non-specific binding (dpm)

The specific binding of tritiated ligand in the presence (B) of compoundwas then converted to a percentage of specific binding of tritiatedligand in the absence (A) of compound:

% Specific binding at 10⁻⁶M=B (dpm)/A(dpm)×100

The percentage displacement of specific binding of trtiated ligand bythe test compound (10⁻⁶M) was then obtained by subtraction of thepercentage specific binding in the presence of compound from thepercentage specific binding in the absence of compound, which is takenas the maximum binding and so equals 100%:

% Displacement at 10⁻⁶M=100−% Specific binding at 10⁻⁶M.

The values given below in Table 2 for examples 6 to 76 are %displacement of specific binding of tritiated ligand by 10⁻⁶M testcompound and represent results from one test only. IA refers to <50%displacement.

TABLE 2 Example No. DA uptake 5-HT uptake NA uptake 6 112% 86% 101%  7 69% 85% IA 8 IA 62% IA 9  60% 75% IA 10  85% 57% IA 11 102% 57% IA 12121% 77% 95% 13 104% 92% 92% 14 103% 96% 80% 15 115% 102%  99% 16 116%102%  56% 17 112% 95% 63% 18 106% 95% 63% 19 107% 89% IA 20 105% 104% 91% 21 108% 103%  50% 22  79% IA IA 23  83% IA IA 24  90% IA IA 25 108%95% 66% 26 116% 92% IA 27  84% IA IA 28  71% IA IA 29  74% IA IA 30  79%IA IA 31  63% IA IA 32  69% IA IA 33  99% 63% IA 34 109% 100%  110%  35109% 99% 107%  36 108% 101%  101%  37 110% 101%  102%  38 111% 102%  95%39 108% 100%  58% 40 113% 97% IA 41 107% 98% 79% 42 113% 101%  93% 43113% 101%  93% 44  96% 72% IA 45  96% 59% IA 46  98% 51% IA 47 109% 99%92% 48 101% 94% IA 49  69% 56% IA 50  68% IA IA 51  69% 54% IA 52  74%IA IA 53  80% 71% IA 54  69% IA IA 55  91% IA IA 56  93% IA IA 57  94%IA IA 58  92% IA IA 59  73% IA IA 60 106% IA IA 61  68% IA IA 62  55% IAIA 63 107% 52% IA 64 102% IA IA 65  54% IA IA 66  58% IA IA 67  88% IAIA 68  65% IA IA 69  58% IA IA 70  80% IA 52% 71  96% IA 76% 72  70% IAIA 73  59% IA IA 74  97% 52% IA 75 IA 53% IA 76 IA 81% IA

The types of activity shown in Tables 1 and 2 are indicative ofcompounds having utility in the treatment of the stated indications,particularly Parkinson's disease. Compounds of Formula I may have animproved pharmacological profile over compounds known in the art.

The invention is illustrated by the following Examples which are givenby way of example only. The final product of each of these Examples wascharacterised by one or more of the following procedures: highperformance liquid chromatography; elemental analysis, nuclear magneticresonance spectroscopy, mass spectroscopy and infrared spectroscopy.

EXAMPLE 1

Methylmagnesium iodide was prepared under nitrogen by dropwise additionof a solution of iodomethane (93.8 g) in ether (100 ml) to a stirredsuspension of magnesium turnings (15.9 g) in ether (100 ml) initially atambient temperature then, when the exothermic reaction commenced, atreflux temperature. After the addition was complete the mixture wasstirred for 30 minutes, then a solution of1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (100 g) in ether (80 ml)was added dropwise at ambient temperature. The mixture was stirred atreflux temperature for 3 hours and at ambient temperature for 16 hours.The resulting solid was collected by filtration, washed well with ether,then added in portions to an ice-cold mixture of water (400 ml) andconcentrated hydrochloric acid (250 ml). The resulting mixture washeated at 95° C. for 1 hour with occasional stirring then cooled toambient temperature. The product was extracted into ether (6×150 ml),the extracts were dried (MgSO₄), and the solvent was removed in vacuo.The residue was distilled to give1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone as a pale yellow oil (89.6g), b.p. 116-118° C./0.13 mbar.

A solution of bromine (10.2 ml) in dichloromethane (50 ml) was addeddropwise over 3.5 hours at 10-15° C. under nitrogen to a stirredsolution of 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (47 g) in amixture of methanol (75 ml) and dichloromethane (15 ml). After theaddition was complete, the mixture was stirred at ambient temperaturefor 2.5 hours, then poured onto ice-water (500 ml). The aqueous layerwas separated and washed with dichloromethane (3×100 ml), then thecombined organic solutions were washed with saturated aqueous sodiumhydrogen carbonate solution (2×100 ml) and water (100 ml), dried(CaCl₂), and the solvents removed in vacua. The residue was distilled togive 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone as a paleyellow oil (40.2 g), b.p. 156-164° C. at 0.8 mbar.

A solution of imidazolidine-2-thione (4.5 g) in acetone (750 ml ) wasadded to a solution of2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (15 g) in acetone(125 ml), then the stirred mixture was heated under reflux for 10minutes, and allowed to cool to ambient temperature. The resulting solidwas collected by filtration, washed with ethanol (50 ml) and dried invacuo at 60° C. for 4 hours to give1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(2-imidazolin-2-ylthio)ethanonehydrobromide as a white solid (16.3 g), m.p. 156-158° C.

A stirred suspension of1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(2-imidazolin-2-ylthio)ethanonehydrobromide (5 g) in acetic acid (20 ml) was heated under reflux for 18hours then allowed to cool to ambient temperature. The solvent wasremoved in vacuo, the residue was allowed to stand at ambienttemperature for 24 hours, and the resulting solid was triturated withether (50 ml), collected by filtration, washed with ether (50 ml) anddried in vacuo at 50° C. for 3 hours to give3-[1-(3,4-dichlorophenyl)cyclobuty]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide as a white solid (4.5 g), m.p. 241-244° C.

EXAMPLE 2

A solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (238 g) in ether(500 ml) was added at reflux temperature under nitrogen over 40 minutesto stirred ethereal methylmagnesium iodide solution (3M; 701 ml). Afterthe addition was complete, the mixture was stirred at reflux temperaturefor 3 hours and at ambient temperature for 60 hours. The resulting solidwas collected by filtration, washed well with ether, and added inportions to a stirred mixture of crushed ice (1 l) and concentratedhydrochloric acid (1 l). The resulting mixture was stirred at 95° C. for1 hour then cooled to ambient temperature. The product was extractedinto dichloromethane (3×250 ml), and the combined extracts were washedwith water (3×200 ml), dried (MgSO₄), and the solvent was removed invacuo. The residue was distilled to give1-[1-(4-chlorophenyl)cyclobutyl]ethanone as a brown oil (198.1 g), b.p.95-100° C. at 0.3 mbar.

A solution of bromine (35 ml) in chloroform (150 ml) was added dropwiseover 3 hours to a stirred mixture of1-[1-(4-chlorophenyl)cyclobutyl]ethanone (150 g), chloroform (50 ml) andmethanol (235 ml). When the addition was complete, the mixture wasstirred at ambient temperature for a further 3 hours, then it wasdiluted with ice-cold water (750 ml). The product was extracted intodichloromethane (3×200 ml), and the combined extracts were washed withsaturated aqueous sodium hydrogen carbonate solution (3×100 ml) andwater (100 ml), dried (MgSO₄), and the solvents removed in vacuo, toleave 2-bromo-1-[1-(4-chlorophenyl)cyclobutyl]ethanone as an oil whichwas used without further purification.

A solution of 2-bromo-1-[1-(4-chlorophenyl)cyclobutyl]ethanone (2.9 g)in acetone (25 ml) was added to a solution of3,4,5,6-tetrahydropyrimidine-2-thiol (1.2 g) in acetone (150 ml), thenthe mixture was heated under reflux for 1 hour, and allowed to cool toambient temperature. The resulting solid was collected by filtration anddried in vacuo at ambient temperature to give1-[1-(4-chlorophenyl)cyclobutyl]-2-(3,4,5,6-tetrahydropyrimidin-2-ylthio)ethanonehydrobromide as a white solid (3.5 g), m.p. 205° C.

A suspension of1-[1-(4-chlorophenyl)cyclobutyl]-2-(3,4,5,6-tetrahydropyrimidin-2-ylthio)ethanonehydrobromide (3.4 g; prepared in a similar manner to that describedabove) in acetic acid (8.5 ml) was heated under reflux for 16 hours,then allowed to cool to ambient temperature. The solvent was removed invacuo, the residue was triturated with ether (50 ml), and the resultingsolid was collected by filtration, washed with ether (50 ml), and driedin vacuo at ambient temperature to give3-[1-(4-chlorophenyl)cyclobutyl]-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidinehydrobromide as a white solid (3.0 g), m.p. 256° C.

EXAMPLE 3

A solution of 2-bromo-1-[1-(4-chlorophenyl)cyclobutyl]ethanone (2.9 g)in acetone (25 ml) was added to a solution of imidazolidine-2-thione (10g) in acetone (150 ml), then the mixture was heated under reflux for 1.5hours, and allowed to cool to ambient temperature. The resulting solidwas collected by filtration and dried in vacuo at ambient temperature togive 1-[1-(4-chlorophenyt)cyclobutyl]-2-(2-imidazolin-2-ylthio)ethanonehydrobromide as a white solid (2.3 g), m.p. 151-153° C.

A suspension of 1-[1-(4-chlorophenyl)cyclobutyl]-2-(2-imidazolin-2ylthio)ethanone hydrobromide (2.4 g—prepared in a manner similar to thatdescribed above) in acetic acid (6 ml) was heated under reflux for 16hours, then allowed to cool to ambient temperature. The solvent wasremoved in vacuo, the residue was triturated with ether (50 ml), and theresulting solid was collected by filtration, washed with ether (50 ml),dried in vacuo at ambient temperature, and recrystallised from methanol.The resulting solid was collected by filtration and dried in vacuo atambient temperature to give3-[1-(4-chlorophenyl)cyclobutyl]-5,6-dihydroimidazo-[2,1-b]thiazolehydrobromide as a white solid (1.4 g), m.p. 258-260° C.

EXAMPLE 4

A solution of 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (3.2g) in acetone (25 ml) was added to a solution of3,4,5,6-tetrahydropyrimidine-2-thiol (1.2 g) in acetone (150 mL), thenthe mixture was heated under reflux for 0.5 hour, and allowed to cool toambient temperature. The resulting solid was collected by filtration anddried in vacuo at ambient temperature to give1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3,4,5,6-tetrahydropyrimidin-2-ylthio)ethanonehydrobromide as a white solid (3.9 g), m.p. 203-204° C.

A suspension of1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3,4,5,6-tetrahydropyrimidin-2-ylthio)ethanonehydrobromide (2.0 g—prepared in a manner similar to that describedabove) in acetic acid (7 ml) was heated under reflux for 16 hours, thenallowed to cool to ambient temperature. The solvent was removed invacuo, the residue was triturated with ether (50 ml), and the resultingsolid was collected by filtration, washed with ether (50 ml), and driedin vacuo at ambient temperature to give3-[1-(3,4-dichlorophenyl)cyclobutyl]-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidinehydrobromide as a white solid (1.7 g), m.p. 269° C.

EXAMPLE 5

A solution of 2-naphthylacetonitrile (10 g) and 1,3-dibromopropane (144g) in a mixture of ether (350 ml) and dimethylsulphoxide (150 ml) wasadded dropwise at 20-25° C. under nitrogen over 2 hours to a stirredmixture of finely-powdered potassium hydroxide (150 g), 18-Crown-6 (1.3g) and dimethylsulphoxide (570 ml). After the addition was complete, themixture was cooled to 15° C. and quenched by the slow addition of water(330 ml). Ether (330 ml) was added, and the mixture was filtered throughHyflo Supercel filtration aid. The filter pad was washed well withether, then the aqueous layer of the filtrate was separated, dilutedwith water (500 ml), and washed well with ether. All of the etherealsolutions were combined, washed with water (3×100 ml), and the solventswere removed in vacua. The residue was triturated with ethanol (100 ml)and the resulting solid was collected by filtration and dried in vacuato give 1-(2-naphthyl)cyclobutanecarbonitrile as a white solid (48.7 g),which was used without further purification.

A solution of 1-(2-naphthyl)cyclobutanecarbonitrile (48.2 g) in toluene(100 ml) was added dropwise under nitrogen to a stirred solution ofmethylmagnesium iodide [prepared in the usual manner from iodomethane(22 ml) and magnesium (8.16 g)] in ether (60 ml), then the mixture wasstirred at ambient temperature for 18 hours. The resulting solid wascollected by filtration, washed with ether (50 ml), and added inportions to a mixture of concentrated hydrochloric acid (125 ml) andwater (200 ml). The mixture was heated at 100° C. with occasionalstirring for 10 minutes, then it was cooled to ambient temperature. Theproduct was extracted into toluene (3×200 ml), then the extracts werewashed with water (200 ml), and the solvent was removed in vacua. Theresidue was triturated with petroleum ether (b.p. 40-60° C.) (100 ml),and the resulting solid was collected by filtration and dried in vacuoto give 1-[1-(2-naphthyl)cyclobutyl]ethanone as a yellow solid (35 g)which was used without further purification.

Bromine (2.6 ml) was added dropwise over 1 hour at ambient temperatureto a stirred solution of 1-[1-(2-naphthyl)cyclobutyl]ethanone (11.25 g)in ether (300 ml). After the addition was complete and the brominecolour had dissipated, the mixture was stirred at ambient temperaturefor a further 0.5 hour then it was washed with water (100 ml), saturatedaqueous sodium hydrogen carbonate solution (2×100 ml) and water (100ml), dried (MgSO₄), and the solvent removed in vacuo to give2-bromo-1-[1-(2-naphthyl)cyclobutyl]ethanone as an oil which was usedwithout purification.

A mixture of the crude 2-bromo-1-[1-(2-naphthyl)cyclobutyl]ethanonedescribed above, imidazolidine-2-thione (5.1 g), ethanol (60 ml) andacetic acid (40 ml) was heated under reflux for 18 hours then allowed tocool to ambient temperature. The solvents were removed in vacuo and theresidue was triturated with a hot mixture of ethyl acetate (100 ml) andacetone (20 ml). The resulting solid was collected by filtration, washedwith ethyl acetate (50 ml), dried in vacuo at 60° C., then crystallisedfrom ethanol. The resulting solid was collected by filtration, washedwith ethanol (30 ml), and dried in vacuo at 60° C. to give3-[1-(2-naphthyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide as pale yellow prisms (10 g), m.p. 239-241° C.

EXAMPLE 6

1,4-Dibromobutane (106 ml) was added dropwise over 1 hour at 70-80° C.under nitrogen to a stirred mixture of 3,4-dichlorophenylacetonitrile(150 g), benzyltriethylammonium chloride (2 g) and 50% aqueous sodiumhydroxide solution (300 ml). When the addition was complete the mixturewas stirred at 70-80° C. for 2 hours, then it was cooled to ambienttemperature. Ether (400 ml) and water (200 ml) were added, and thelayers were separated. The aqueous phase was washed with ether (2×200ml), then the combined ethereal solutions were dried (MgSO₄) and thesolvent was removed in vacuo. The residue was distilled to give1-(3,4-ichlorophenyl)cyclopentanecarbonitrile as a pale yellow oil (135g), b.p. 132-140° C./0.4 mbar.

Methylmagnesium iodide (3M solution in ether; 100 ml) was added dropwiseat 0° C. under nitrogen to a stirred solution of1-(3,4-dichlorophenyl)cyclopentanecarbonitrile (48 g) in ether (100 ml),then the mixture was stirred at ambient temperature for 24 hours. Theresulting solid was collected by filtration, washed well with ether, andadded in portions to an ice-cold mixture of water (200 ml) andconcentrated hydrochloric acid (125 ml). The mixture was heated at 95°C. with occasional stirring for 1 hour, then it was allowed to cool toambient temperature. The product was extracted into ether (5×100 ml),then the combined extracts were washed with water (2×100 ml), dried(MgSO₄), and the solvent was removed in vacuo. The residue was distilledto give 1-[1-(3,4-dichlorophenyl)cyclopentyl]ethanone as a pale yellowoil (31.9 g), b.p. 124-128° C/0.5 mbar.

A solution of bromine (6.1 ml) in dichloromethane (50 ml) was addeddropwise over 3 hours at 10-15° C. under nitrogen to a stirred solutionof 1-[1-(3,4-dichlorophenyl)cyclobuty]ethanone (31.9 g) in a mixture ofmethanol (60 ml) and dichloromethane (10 ml). When the addition wascomplete, the mixture was stirred at ambient temperature for 2.5 hours,then it was poured into an excess of ice-water. The product wasextracted into dichloromethane (3×100 ml), then the combined extractswere washed with saturated aqueous sodium hydrogen carbonate solution(2×100 ml) followed by water (100 ml), dried (CaCl₂), and the solventremoved in vacuo. The residue was distilled, and the fraction ofb.p. >174° C./1.3 mbar was collected and redistilled. Material ofb.p. >182° C./2.6 mbar in this second distillation was collected andredistilled to give2-bromo-1-[1-(3,4-dichlorophenyl)cyclopentyl]ethanone as a pale yellowoil (11.8 g), b.p. 156-162° C./0.4 mbar.

A mixture of 2-bromo-1-[1-(3,4-dichlorophenyl)cyclopentyl]ethanone (0.5g), imidazolidine-2-thione (0.16 g), ethanol (3 ml) and acetic acid (2ml) was heated under reflux for 18 hours then allowed to cool to ambienttemperature. The solvents were removed in vacuo and the residuecrystallised from a 1:1 mixture of ethyl acetate and ethanol. Theresulting product was collected by filtration, washed with ethanol (3ml) and dried in vacuo at 60° C. to give3-[1-(3,4-dichlorophenyl)cyclopentyl]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide as white microneedles (0.27 g), m.p. 230-232° C.

EXAMPLE 7

A solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (35 g) intoluene (100 ml) was added dropwise at reflux temperature under nitrogento a stirred solution of phenethylmagnesium bromide [prepared in theusual manner from phenethyl bromide (45.6 g) and magnesium (6.24 g)] inether (100 ml). When the addition was completed, ether was distilledfrom the mixture until the internal temperature rose to 110° C., thenstirring at this temperature was continued for 18 hours. The mixture wasthen cooled to ambient temperature, added to a mixture of ice (200 g)and concentrated hydrochloric acid (100 ml), heated at 95° C. withoccasional stirring for 4 hours, and cooled to ambient temperature. Theproduct was extracted into dichloromethane (3×200 ml), and the combinedextracts were washed with water (100 ml), saturated aqueous sodiumcarbonate solution (2×100 ml) and water (100 ml), dried (Na₂SO₄), andthe solvent was removed in vacuo. The residue was distilled to give1-[1-(4-chlorophenyl)cyclobutyl]-3-phenylpropan-1-one as a yellow oil(38.8 g), b.p. 178-181° C./1.3 mbar.

Bromine (0.52 ml) was added dropwise over 20 minutes at ambienttemperature to a stirred solution of1-[1-(4-chlorophenyl)cyclobutyl]-3-phenylpropan-1-one (3 g) in ether (50ml). After the addition was complete and the bromine colour haddissipated, the mixture was stirred at ambient temperature for a further1 hour then it was washed with water (30 ml), saturated aqueous sodiumhydrogen carbonate solution (2×30 ml) and water (30 ml), dried (MgSO₄),and the solvent removed in vacuo to give2-bromo-1-[1-(4-chlorophenyl)cyclobutyl]-3-phenylpropan-1-one as an oilwhich was used without purification.

A mixture of the crude2-bromo-1-[1-(4-chlorophenyl)cyclobutyl]-3-phenylpropan-1-one describedabove, imidazolidine-2-thione (1.02 g), ethanol (15 ml) and acetic acid(10 ml) was heated under reflux for 18 hours then allowed to cool toambient temperature. The solvents were removed in vacuo and the residuewas dried by azeotropic distillation with ethanol (50 ml) followed byethyl acetate (50 ml). The solid remaining after removal of residualsolvent in vacuo was crystallised from ethanol. The resulting productwas collected by filtration, washed with ethanol (10 ml) and dried invacuo at 60° C. to give2-benzyl-3-[1-(4-chlorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]-thiazolehydrobromide as white microneedles (2 g), m.p. 255-257° C.

EXAMPLE 8

A solution of 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (15 g) inether (50 ml) was added dropwise to a stirred solution of3-methoxypropylmagnesium bromide [prepared in the usual manner from1-bromo-3-methoxypropane (15.3 g) and magnesium (2.4 g)] in ether (55ml), then the mixture was stirred at reflux temperature for 2.5 hours,cooled to ambient temperature, and added to a mixture of crushed ice(100 g) and concentrated hydrochloric acid (80 ml). The resultingmixture was heated at 95° C. with occasional stirring for 1.5 hours,then it was allowed to stand at ambient temperature for 48 hours. Theproduct was extracted into ether (3×100 ml), and the combined extractswere washed with water (100 ml), saturated aqueous sodium hydrogencarbonate solution (100 ml) and water (100 ml), dried (MgSO₄), and thesolvent was removed in vacua. The residue was distilled to give1-[1-(3,4-dichlorophenyl)cyclobutyl]-4-methoxybutanone as a pale yellowoil (16.4 g), b.p. 138-147° C./0.5 mbar.

Bromine (0.35 ml) was added dropwise over 20 minutes at ambienttemperature to a stirred solution of1-[1-(3,4-dichlorophenyl)cyclobutyl]-4-methoxybutan-1-one (2 g) in ether(40 ml). After the addition was complete and the bromine colour haddissipated, the mixture was stirred at ambient temperature for a further1 hour then it was washed with water (30 ml), saturated aqueous sodiumhydrogen carbonate solution (2×30 ml) and water (30 ml), dried (MgSO₄),and the solvent removed in vacuo to give2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-4-methoxybutan-1-one as anoil which was used without purification.

A mixture of the crude2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-4-methoxybutan-1-onedescribed above, imidazolidine-2-thione (0.68 g), ethanol (15 ml) andacetic acid (10 ml) was heated under reflux for 18 hours then allowed tocool to ambient temperature. The solvents were removed in vacua and theresidue was dried by azeotropic distillation with ethanol (50 ml)followed by ethyl acetate (20 ml). The solid remaining after removal ofresidual solvent in vacuo was crystallised from a 2:1 mixture of ethanoland ethyl acetate. The resulting product was collected by filtration,washed with ethanol (10 ml) and dried in vacuo at 60°0 C. to give3-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(2-methoxyethyl)-5,6-dihydroimidazo[2,1-b]-thiazolehydrobromide as colourless prisms (1.39 g), m.p. 227-229° C.

EXAMPLE 9

A solution of 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (6.56 g) intoluene (100 ml) was added dropwise under nitrogen to a stirred solutionof benzylmagnesium chloride [prepared in the usual manner from benzylchloride (5 ml) and magnesium (1.08 g)] in ether (100 ml). When theaddition was complete, ether was distilled from the mixture until theinternal temperature rose to 95° C., then the mixture was stirred atthis temperature for 19 h, cooled to ambient temperature, and quenchedby the dropwise addition of water (30 ml) followed by concentratedhydrochloric acid (10 ml). The mixture was stirred at 95° C. for 2.5hours, then it was cooled to ambient temperature. The organic phase wasseparated, washed with water (2×100 ml) and saturated brine (100 ml),dried (Na₂SO₄), and the solvent was removed in vacuo. The residue waspurified via flash chromatography over silica using a 5:95 mixture ofethyl acetate and toluene as eluant. Appropriate fractions were combinedand the solvents removed in vacuo to give1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-phenyl)ethanone]-2-phenylethanoneas a colourless oil (5.08 g) which solidified slowly at ambienttemperature to give a colourless solid, m.p. 53-55° C.

Phenyltrimethylammonium tribromide (4.02 g) was added in portions at−10° C. to a stirred solution of1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-phenylethanone (3.41 g) intetrahydrofuran (100 ml). The mixture was stirred at ambient temperaturefor 4 hours, then it was filtered, and the solvent removed in vacuo. Theresidue was purified via flash chromatography over silica using a 3:97mixture of ethyl acetate and petroleum ether (b.p. 60-80° C.) as eluant.Appropriate fractions were combined, and the solvents removed in vacuoto give 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-phenylethanone asa colourless oil (3.8 g).

A mixture of2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-phenylethanone (3.8 g),imidazolidine-2-thione (0.97 g), ethanol (70 ml) and acetic acid (40 ml)was heated under reflux for 20 hours then allowed to cool to ambienttemperature. The solvents were removed in vacuo and the residue wascrystallised from ethanol. The resulting product was collected byfiltration, washed with ethanol (10 ml) and dried in vacuo at 100° C. togive3-[1-(3,4-dichlorophenyl)cyclobutyl]-2-phenyl-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide as a pale brown solid (1.43 g), m.p. 280° C. (decomposes).

EXAMPLE 10

A solution of 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (6.56 g) intoluene (100 ml) was added dropwise under nitrogen to a stirred solutionof 4-chlorobenzylmagnesium chloride [prepared in the usual manner from4-chlorobenzyl chloride (9.07) and magnesium (1.08 g)] in ether (100ml). When the addition was complete, ether was distilled from themixture until the internal temperature rose to 95° C., then the mixturewas stirred at this temperature for 19 h, cooled to ambient temperature,and quenched by the dropwise addition of water (50 ml) followed byconcentrated hydrochloric acid (10 ml). The mixture was stirred at 95°C. for 3 hours, then it was cooled to ambient temperature. The organicphase was separated, washed with water (100 ml) and saturated brine (100ml), dried (Na₂SO₄), and the solvent was removed in vacuo. The residuewas purified via flash chromatography over silica using 1:9-1:4 mixturesof ethyl acetate and petroleum ether (b.p. 60-80° C.) as eluant.Appropriate fractions were combined and the solvents removed in vacuo togive 2-(4-chlorophenyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone asa yellow oil (7.51 g) which solidified slowly at ambient temperature togive a yellow solid, m.p. 82-84° C.

Phenyltrimethylammonium tribromide (6.59 g) was added in portions at −5°C. to a stirred solution of2-(4-chlorophenyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (6.2 g)in tetrahydrofuran (150 ml). The mixture was stirred at ambienttemperature for 4 hours, allowed to stand at ambient temperature for afurther 48 hours, then it was filtered, and the solvent removed invacuo. The residue was purified via flash chromatography over silicausing a 3:97 mixture of ethyl acetate and petroleum ether (b.p. 60-80°C.) as eluant. Appropriate fractions were combined, and the solventsremoved in vacuo. The residue was triturated with petroleum ether (b.p.60-80° C.) (30 ml) and the resulting solid was collected by filtrationand dried in vacuo at ambient temperature to give2-bromo-2-(4-chlorophenyl)1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanoneas a colourless solid (4.83 g), m.p. 109-110° C.

A mixture of2-bromo-2-(4-chlorophenyl)1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone(3.68 g), imidazolidine-2-thione (0.87 g), ethanol (60 ml) and aceticacid (35 ml) was heated under reflux for 18 hours then allowed to coolto ambient temperature. The solvents were removed in vacuo and theresidue was triturated with ethanol (30 ml). The resulting solid wascollected by filtration and crystallised from acetic acid. The resultingproduct was collected by filtration, washed with acetic acid (10 ml) anddried in vacuo at 100° C. to give2-(4-chlorophenyl)-3-[1-(3,4-dichlorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide as a colourless solid (0.93 g), m.p. 302-304° C.(decomposes).

EXAMPLE 11

A solution of 3,4-dichlorophenylacetonitrile (50 g) and iodomethane (37ml) in ether (to total volume 220 ml) was added dropwise at ambienttemperature over 3 hours to a stirred mixture of finely-powderedpotassium hydroxide (68.3 g), 18-Crown-6 (0.65 g) and dimethylsulphoxide (220 ml). When the addition was complete, the mixture wasstirred at 30° C. for 2 hours, cooled to 15° C., and quenched at thattemperature by the dropwise addition of water (185 ml). The product wasextracted into ether (3×300 ml), and the combined extracts were washedwith water (200 ml), 5M hydrochloric acid (200 ml), water (200 ml) andsaturated brine (200 ml), dried (MgSO₄), and the solvent was removed invacuo. The residue was distilled to give2-(3,4-dichlorophenyl)-2-methylpropionitrile as a pale yellow oil (37.6g), b.p. 116-120° C./2.7-3.3 mbar.

A solution of 2-(3,4-dichlorophenyl)-2-methylpropionitrile (12.8 g) inether (100 ml) was added dropwise at −10° C. under nitrogen over 20minutes to stirred ethereal methylmagnesium iodide solution (3M; 30 ml),then the mixture was stirred at reflux temperature for 2 hour and atambient temperature for 18 hours. The resulting solid was collected byfiltration, washed well with ether, and added in portions to a mixtureof ice-cold water (100 ml) and concentrated hydrochloric acid (50 ml).The resulting mixture was heated at 95° C. with occasional stirring for1 hour, then cooled to ambient temperature. The product was extractedinto dichloromethane (3×100 ml), then the combined extracts were dried(CaCl₂), and the solvents were removed in vacuo to give3-(3,4-dichlorophenyl)-3-methylbutan-2-one as a pale brown oil (9.07 g)which was used without further purification.

A solution of bromine (1.84 ml) in ether (25 ml) was added dropwise over1 hour at ambient temperature to a stirred solution of3-(3,4-dichlorophenyl)-3-methylbutan-2-one (8.24 g) in ether (250 ml).After the addition was complete and the bromine colour had dissipated,the mixture was stirred at ambient temperature for a further 30 minutesthen it was washed with water (100 ml), saturated aqueous sodiumhydrogen carbonate solution (2×100 ml) and water (100 ml), dried(MgSO₄), and the solvent removed in vacuo to give1-bromo-3-(3,4-dichlorophenyl)-3 methylbutan-2-one as an oil (9.57 g)which was used without purification.

A mixture of the crude1-bromo-3-(3,4-dichlorophenyl)-3-methylbutan-2-one described above (3.1g), imidazolidine-2-thione (1.2 g), ethanol (1.02 ml) and acetic acid (8ml) was heated under reflux for 22 hours then allowed to cool to ambienttemperature. The solvents were removed in vacuo and the residue wastriturated with hot ethyl acetate (80 ml). The resulting solid wascollected by filtration, washed with ethyl acetate (20 ml), dried invacuo at 50° C., then crystallised from ethanol. The resulting productwas collected by filtration, washed with ethanol (5 ml) and dried invacuo at 50° C. to give3-[1-(3,4-dichlorophenyl)-1-methylethyl]-5,6-dihydroimidazo[2,1-b]-thiazolehydrobromide as an off-white solid (0.95 g), m.p. 266-270° C.(decomposes).

EXAMPLE 12

A mixture of benzo[b]thiophen-2-methanol (32.8 g) and thionyl chloride(29.7 g) was heated under reflux under nitrogen for2-chloromethylbenzo[b]thiophene as a yellow oil (23.8 g), b.p. 108-110°C./1.4 mbar.

A mixture of 2-chloromethylbenzo[b]thiophene (21 g), potassium cyanide(11.7 g), 1,4-dioxane (200 ml) and water (100 ml) was stirred and heatedunder reflux for 4 hours, then cooled to ambient temperature and dilutedwith water (200 ml). The product was extracted into toluene (3×200 ml),then the combined extracts were washed with water (2×300 ml), dried(Na₂SO₄), and the solvents were removed in vacuo. The residue waspurified via flash chromatography over silica using a 1:4 mixture ofethyl acetate and petroleum ether (b.p. 60-80° C.) as eluant.Appropriate fractions were combined and the solvents were removed invacuo to give benzo[b]thiophen-2-acetonitrile as a yellow solid (8.9 g),m.p. 59-61° C.

A solution of benzo[b]thiophen-2-acetonitrile (8.05 g) and1,3-dibromopropane (5.2 ml) in ether (50 ml) was added dropwise undernitrogen over 1 hour to a stirred, ice-cold suspension offinely-powdered potassium hydroxide (13.53 g) in dimethyl sulphoxide(100 ml). When the addition was complete, the mixture was stirred atambient temperature for 4 hours, then it was added to ice-cold water(200 ml). The resulting mixture was acidified to pH4 by the addition ofconcentrated hydrochloric acid, then the product was extracted intoether (3×200 ml). The combined extracts were washed with water (500 ml),dried (MgSO₄), and the solvent was removed in vacuo to give1-(benzo[b]thiophen-2-yl)cyclobutanecarbonitrile as a red oil (8.16 g)which was used without purification.

A solution of 1-(benzo[b]thiophen-2-yl)cyclobutanecarbonitrile (7.7 g)in ether (50 ml) was added dropwise at ambient temperature undernitrogen to stirred ethereal methylmagnesium iodide solution (3M; 18ml). When the addition was complete, the mixture was stirred at refluxtemperature for 3.5 hours, then it was cooled to ambient temperature.The resulting solid was collected by filtration, washed well with ether,and added in portions to 5M hydrochloric acid (143 ml). The resultingmixture was heated at 95° C. with occasional stirring for 1.5 hours,then allowed to stand at ambient temperature for 18 h. The product wasextracted into dichloromethane (3×200 ml), then the combined extractswere washed with water (2×400 ml) and saturated aqueous sodium hydrogencarbonate solution (400 ml), dried (Na₂SO₄), and the solvent removed invacuo to give 1-[1-(benzo[b]thiophen-2 yl)cyclobutyl]ethanone as a brownoil (5 g) which was used without purification.

Phenyltrimethylammonium tribromide (1.72 g) was added in portions at−20° C. to a stirred solution of1-[1-(benzo[b]thiophen-2-yl)cyclobutyl]ethanone (1.05 g) intetrahydrofuran (50 ml). The mixture was stirred at ambient temperaturefor 3 hours, then it was filtered, and allowed to stand at ambienttemperature for a further 18 hours. The mixture was filtered once more,and the solvent was removed in vacuo. The residue was purified via flashchromatography over silica using a 1:49 mixture of ether and petroleumether (b.p. 40-60° C.) as eluant. Appropriate fractions were combined,and the solvents removed in vacuo to give1-[1-(benzo[b]thiophen-2-yl)cyclobutyl]-2-bromoethanone as an oil (0.46g).

A mixture of 1-[1-(benzo[b]thiophen-2-yl)cyclobutyl]-2-bromoethanone(0.42 g), imidazolidine-2-thione (0.14 g), ethanol (15 ml) and aceticacid (10 ml) was heated under reflux for 18 hours then allowed to coolto ambient temperature. The solvents were removed in vacuo and theresidue was triturated with ether (30 ml). The resulting solid wascollected by filtration, dried in vacuo at 40° C. and crystallised fromethanol. The resulting product was collected by filtration, washed withethanol (3 ml) and dried in vacuo at 40° C. to give3-[1-(benzo[b]thiophen-2-yl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide as an off-white solid (0.28 g), m.p. 240-242° C.

EXAMPLES 13-55

General Procedure

Aliquots of stock solutions of2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (prepared in amanner similar to that described in Example 1) or of2-bromo-1-[1-(2-naphthyl)cyclobutyl]ethanone (prepared in a mannersimilar to that described in Example 5) in absolute ethanol (0.083M,1.20 ml, 0.10 mmol) were added to a number of 20 ml screw-top vials,each containing the appropriate thiourea of Formula III (0.10 mmol) andacetic acid (0.80 ml). The reaction vials were sealed with a screw-capand heated at 85° C. for 20 hours with agitation on an orbital shaker.Each reaction mixture was analysed by HPLC-MS and then diluted with anappropriate volume of digol so as to give a 10⁻³M solution of the activecompound for testing in the in vitro biological assays.

The following compounds were prepared, as the major component in thereaction mixture, by the above method (HPLC purities and MS molecularions indicated):

EXAMPLE 13

An unresolved mixture of3-[1-(3,4-dichlorophenyl)cyclobutyl]-5-methyl-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide and3-[1-(3,4-dichlorophenyl)cyclobutyl]-6-methyl-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide, HPLC 97.6% (3.17 min); m/z 339 (MH⁺).

EXAMPLE 14

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-methyl-2-methylimino-2,3dihydrothiazole hydrobromide, HPLC 92.4% (3.03 min); m/z 327 (MH⁺).

EXAMPLE 15

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-ethyl-2-ethylimino-2,3-dihydrothiazolehydrobromide, HPLC 94.3% (3.35 min); m/z 355 (MH⁺).

EXAMPLE 16

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-propyl-2-propylimino-2,3-dihydrothiazolehydrobromide, HPLC 88.7% (3.83 min); m/z 383 (MH⁺).

EXAMPLE 17

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-isopropyl-2-isopropylimino-2,3-dihydrothiazolehydrobromide, HPLC 86.0% (3.83 min); m/z 383 (MH⁺).

EXAMPLE 18

3-Butyl-2-butylimino-4-[1-(3,4-dichlorophenyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 85.7% (4.27 min); m/z 411 (MH⁺).

EXAMPLE 19

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-isobutyl-2-isobutylimino-2,3-dihydrothiazolehydrobromide, HPLC 92.1% (3.99 min); m/z 411 (MH⁺).

EXAMPLE 20

3-Allyl-2-allylimino-4-[1-(3,4-dichlorophenyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 86.1% (3.58 min); m/z 379 (MH⁺).

EXAMPLE 21

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-cyclopropylmethyl-2-cyclopropylmethylimino-2,3-dihydrothiazolehydrobromide, HPLC 67.9% (3.93 min); m/z 407 (MH⁺).

EXAMPLE 22

3-Benzyl-2-benzylimino-4-[1-(3,4-dichlorophenyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 90.5% (4.79 min); m/z 479 (MH⁺).

EXAMPLE 23

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(4-fluorobenzyl)-2-(4-fluorobenzylimino)-2,3-dihydrothiazolehydrobromide, HPLC 89.8% (5.00 min); m/z 515 (MH⁺).

EXAMPLE 24

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-phenethyl-2-phenethylimino-2,3-dihydrothiazolehydrobromide, HPLC 91.4% (5.26 min); m/z 507 (MH⁺).

EXAMPLE 25

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(3-pyridylmethyl)-2-(3-pyridylmethylimino)-2,3-dihydrothiazolehydrobromide, HPLC 79.4% (3.63 min); m/z 481 (MH⁺).

EXAMPLE 26

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-furfuryl-2-furfurylimino-2,3-dihydrothiazolehydrobromide, HPLC 92.2% (4.57 min); m/z 459 (MH⁺).

EXAMPLE 27

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-phenyl-2-phenylimino-2,3-dihydrothiazolehydrobromide, HPLC 86.8% (4.94 min); m/z 451 (MH⁺).

EXAMPLE 28

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(p-tolyl)-2-(ptolylimino)-2,3-dihydrothiazolehydrobromide, HPLC 85.9% (5.22 min); m/z 479 (MH⁺).

EXAMPLE 29

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(o-tolyl)-2-(o-tolylimino)-2,3-dihydrothiazolehydrobromide, HPLC 92.1% (5.22 min); m/z 479 (MH⁺).

EXAMPLE 30

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(3-trifluoromethylphenyl)-2-(3-trifluoromethylphenylimino)-2,3-dihydrothiazolehydrobromide, HPLC 67.6% (5.16 min); m/z 587 (MH⁺).

EXAMPLE 31

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(2,4-xylyl)-2-(2,4-xylylimino)-2,3-dihydrothiazolehydrobromide, HPLC 76.8% (5.47 min); m/z 507 (MH⁺).

EXAMPLE 32

4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(4-ethoxyphenyl)-2-(4-ethoxyphenylimino)-2,3-dihydrothiazolehydrobromide, HPLC 68.2% (5.09 min); m/z 539 (MH⁺).

EXAMPLE 33

4-[1-(3,4-Dichlorophenyi)cyclobutyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydnothiazolehydrobromide, HPLC 100.0% (4.05 min); m/z 627 (MH⁺).

EXAMPLE 34

3-[1-(2-Naphthyl)cyclobutyl]-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidinehydrobromide, HPLC 50.9% (3.17 min); m/z 321 (MH⁺).

EXAMPLE 35

An unresolved mixture of5-methyl-3-[1-(2-naphthyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide and6-methyl-3-[1-(2-naphthyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide, HPLC 90.4% (3.15 min); m/z 321 (MH⁺).

EXAMPLE 36

3-Methyl-2-methylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 87.1% (3.04 min); m/z 309 (MH⁺).

EXAMPLE 37

3-Ethyl-2-ethylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 89.4% (3.39 min); m/z 337 (MH⁺).

EXAMPLE 38

4-[-(2-Naphthyl)cyclobutyl]-3-propyl-2-propylimino-2,3-dihydrothiazolehydrobromide, HPLC 88.5% (3.82 min); m/z 365 (MH⁺).

EXAMPLE 39

3-Isopropyl-2-isopropylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 90.2% (3.76 min); m/z 365 (MH⁺).

EXAMPLE 40

3-Butyl-2-butylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 94.1% (4.31 min); m/z 393 (MH⁺).

EXAMPLE 41

3-lsobutyl-2-isobutylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 51.2% (4.18 min); m/z 393 (MH⁺).

EXAMPLE 42

3-Allyl-2-allylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 86.3% (3.56 min); m/z 361 (MH⁺).

EXAMPLE 43

3-Cyclopropylmethyl-2-cyclopropylmethylimino4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 89.8% (3.90 min); m/z 389 (MH⁺).

EXAMPLE 44

3-Benzyl-2-benzylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 85.8% (4.60 min); m/z 461 (MH⁺).

EXAMPLE 45

3-(4-Fluorobenzyl)-2-(4-fluorobenzylimino)-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 84.7% (4.87 min); m/z 497 (MH⁺).

EXAMPLE 46

4-1-(2-Naphthyl)cyclobutyl]-3-phenethyl-2-phenethylimino-2,3-dihydrothiazolehydrobromide, HPLC 87.2% (4.99 min); m/z 489 (MH⁺).

EXAMPLE 47

4-[1-(2-Naphthyl)cyclobutyl]-3-(3-pyridylmethyl)-2-(3-pyridylmethylimino)-2,3-dihydrothiazolehydrobromide, HPLC 68.6% (3.56 min); m/z 463 (MH⁺).

EXAMPLE 48

3-Furfuryl-2-furfurylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 90.6% (4.44 min); m/z 441 (MH⁺).

EXAMPLE 49

4-[1-(2-Naphthyl)cyclobutyl]-3-phenyl-2-phenylimino-2,3-dihydrothiazolehydrobromide, HPLC 87.7% (4.93 min); m/z 433 (MH⁺).

EXAMPLE 50

4-[1-(2-Naphthyl)cyclobutyl]-3-(p-tolyl)-2-(p-tolylimino)-2,3-dihydrothiazolehydrobromide, HPLC 79.8% (5.20 min); m/z 461 (MH⁺).

EXAMPLE 51

4-[1-(2-Naphthyl)cyclobutyl)-3-(o-tolyl)-2-(o-tolylimino)-2,3-dihydrothiazolehydrobromide, HPLC 85.1% (5.21 min); m/z461 (MH⁺).

EXAMPLE 52

4-[1-(2-Naphthyl)cyclobutyl]-3-(2,4-xylyl)-2-(2,4-xylylimino)-2,3-dihydrothiazolehydrobromide, HPLC 71.2% (5.44 min); m/z 489 (MH⁺).

EXAMPLE 53

3-Cyclopentyl-2-cyclopentylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 87.4% (5.68 min); m/z 417 (MH⁺).

EXAMPLE 54

3-(4-Ethoxyphenyl)-2-(4-ethoxyphenylimino)-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 76.9% (5.07 min); m/z 521 (MH⁺).

EXAMPLE 55

3-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 89.2% (3.96 min); m/z 609 (MH⁺).

EXAMPLES 56-76

General Procedure

Solutions of a range of ketones of Formula V (0.40 mmol) in ether (8.0ml) were prepared in 20 ml screw-top vials. Bromine (64 mg, 0.40 mmol)was added to each solution, then the vials were sealed with screw-capsand left to stand at ambient temperature for 70 hours. The caps wereremoved and the solvent was removed in vacua. Each residue was thendissolved in ethanol (8 ml) and individual 1 ml aliquots of eachsolution, containing 0.05 mmol of the resulting bromoketone of FormulaIV, were dispensed into 40 ml screw-top vials, each containing aceticacid (1.25 ml) and a solution of a thiourea of Formula III in ethanol(0.05M, 1 ml, 0.05 mmol). The vials were sealed, then heated at 85° C.for 24-29 hours with agitation on an orbital shaker. Each reactionmixture was analysed by HPLC-MS, then the solvents were removed invacuo. The individual residues were dissolved in methanol (4.0 ml), thenfurther diluted with an appropriate volume of digol so as to give a10⁻³M solution of the active compound for testing in the in vitrobiological assays.

The following compounds were prepared, as the major component in thereaction mixture, by the above method (HPLC purities and MS molecularions indicated):

EXAMPLE 56

3-Butyl-2-butylimino-4-[1-(4-chlorophenyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 98.4% (4.20 min); m/z 377 (MH⁺).

EXAMPLE 57

4-[1-(4-Bromophenyl)cyclobutyl]-3-butyl-2-butylimino-2,3-dihydrothiazolehydrobromide, HPLC 63.2% (4.27 min); m/z 421 (MH⁺).

EXAMPLE 58

3-Butyl-2-butylimino-4-[1-(4-methylthiophenyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 86.3% (4.15 min); m/z 389 (MH⁺).

EXAMPLE 59

3-Butyl-2-butylimino-4-[1-(4-phenoxyphenyl)cyclobutyl]-2,3-dihydrothiazolehydrobromide, HPLC 87.2% (4.63 min); m/z 435 (MH⁺).

EXAMPLE 60

3-Butyl-2-butylimino-4-[1-(4-chlorophenyl)cyclopentyl]-2,3-dihydrothiazolehydrobromide, HPLC 70.1% (4.41 min); m/z 391 (MH⁺).

EXAMPLE 61

3-Butyl-2-butylimino-4-(1-phenylcyclohexyl)-2,3-dihydrothiazolehydrobromide, HPLC 73.4% (4.52 min); m/z 371 (MH⁺).

EXAMPLE 62

3-Butyl-2-butylimino-4-[1-(4-chlorophenyl)-1-methylethyl]-2,3-dihydrothiazolehydrobromide, HPLC 93.3% (4.10 min); m/z 365 (MH⁺).

EXAMPLE 63

3-Butyl-2-butylimino-4-[1-(3,4-dichlorophenyl)-1-methylethyl]-2,3-dihydrothiazolehydrobromide, HPLC 90.7% (4.24 min); m/z 399 (MH⁺).

EXAMPLE 64

4-[1-(4-Chlorophenyl)cyclobutyl]-3-phenethyl-2-phenethylimino-2,3-dihydrothiazolehydrobromide, HPLC 89.1% (4.84 min); m/z 473 (MH⁺).

EXAMPLE 65

4-[1-(4-Chlorophenyl)cyclobutyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3dihydrothiazolehydrobromide, HPLC 88.4% (3.91 min); m/z 593 (MH⁺).

EXAMPLE 66

4-[1-(4-Bromophenyl)cyclobutyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazolehydrobromide, HPLC 70.6% (3.99 min); m/z 637 (MH⁺).

EXAMPLE 67

4-[1-(4-Chlorophenyl)cyclopentyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazolehydrobromide, HPLC 90.6% (4.07 min); m/z 607 (MH⁺).

EXAMPLE 68

3-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-4-(1-phenylcyclohexyl)-2,3-dihydrothiazolehydrobromide, HPLC 78.1% (4.01 min); m/z 587 (MH⁺).

EXAMPLE 69

4-[l-(3,4-Dichlorophenyl)-1-methylethyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazolehydrobromide, HPLC 90.6% (3.98 min); m/z 615 (MH⁺).

EXAMPLE 70

3-[1-(4-Bromophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide, HPLC 92.3% (2.96 min); m/z 335 (MH⁺)

EXAMPLE 71

3-[1-(4-Chlorophenyl)cyclopentyl]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide, HPLC 95.7% (3.06 min); m/z 305 (MH⁺)

EXAMPLE 72

3-(1-Phenylcyclohexyl)-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide,HPLC 85.2% (2.91 min); m/z 285 (MH⁺)

EXAMPLE 73

3-[1-(4-Chlorophenyl)-1-methylethyl]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide, HPLC 98.1% (2.68 min); m/z 279 (MH⁺)

EXAMPLE 74

3-[1-(3,4-Dichlorophenyl)-1-methylethyl]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide, HPLC 97.3% (2.92 min); m/z 313 (MH⁺)

EXAMPLE 75

3-[1-(3-Fluorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide, HPLC 95.1% (2.52 min); m/z 275 (MH⁺)

EXAMPLE 76

3-[1-(4-Methylthiophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide, HPLC 91.0% (2.91 min); m/z 303 (MH⁺)

EXAMPLE 77

The use of compounds of the present invention in the manufacture ofpharmaceutical compositions is illustrated by the following description.In this description the term “active compound” denotes any compound ofthe invention but particularly any compound which is the final productof one of the preceding Examples.

a) Capsules

In the preparation of capsules, 10 parts by weight of active compoundand 240 parts by weight of lactose are de-aggregated and blended. Themixture is filled into hard gelatin capsules, each capsule containing aunit dose or part of a unit dose of active compound.

b) Tablets

Tablets are prepared from the following ingredients.

Parts by weight Active compound 10 Lactose 190 Maize starch 22Polyvinylpyrrolidone 10 Magnesium stearate 3

The active compound, the lactose and some of the starch arede-aggregated, blended and the resulting mixture is granulated with asolution of the polyvinyl-pyrrolidone in ethanol. The dry granulate isblended with the magnesium stearate and the rest of the starch. Themixture is then compressed in a tabletting machine to give tablets eachcontaining a unit dose or a part of a unit dose of active compound.

c) Enteric coated tablets

Tablets are prepared by the method described in (b) above. The tabletsare enteric coated in a conventional manner using a solution of 20%cellulose acetate phthalate and 3% diethyl phthalate inethanol:dichloromethane (1:1).

d) Suppositories

In the preparation of suppositories, 100 parts by weight of activecompound is incorporated in 1300 parts by weight of triglyceridesuppository base and the mixture formed into suppositories eachcontaining a therapeutically effective amount of active ingredient.

What is claimed is:
 1. Compounds of formula I

including pharmaceutically acceptable salts thereof in the form ofindividual enantiomers, racemates, or other mixtures of enantiomers, inwhich Ar is phenyl, naphthyl or benzo[b]thiophenyl, each of which may beoptionally substituted by one or more substituents selected from a)halo, b) an alkyl group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, c) an alkoxy group containing 1 to 3carbon atoms optionally substituted by one or more halo, d) an alkylthiogroup containing 1 to 3 carbon atoms optionally substituted by one ormore halo, e) a phenoxy group optionally substituted by one or more haloor f) phenyl optionally substituted by one or more halo; R₁ and R₂,which may be the same or different, independently are a) an alkyl groupcontaining 1 to 6 carbon atoms, b) an alkenyl group containing 3 to 6carbon atoms, c) a cycloalkyl group containing 3 to 7 carbon atoms, d) acycloalkylmethyl group in which the ring contains 3 to 7 carbon atoms,e) an aryl or heteroaryl group optionally substituted by one or moresubstituents selected from i) halo, ii) an alkyl group containing 1 to 3carbon atoms optionally substituted by one or more halo, iii) an alkoxygroup containing 1 to 3 carbon atoms optionally substituted by one ormore halo, iv) an alkylthio group containing 1 to 3 carbon atomsoptionally substituted by one or more halo, f) an arylalkyl orheteroarylalkyl group in which the alkyl chain contains 1 to 3 carbonatoms and in which the aryl or heteroaryl group may optionally besubstituted by one or more substituents selected from i) halo, ii) analkyl group containing 1 to 3 carbon atoms optionally substituted by oneor more halo, iii) an alkoxy group containing 1 to 3 carbon atomsoptionally substituted by one or more halo, iv) an alkylthio groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo; or R₁ and R₂ form an alkylene chain optionally substituted by oneor more alkyl groups each containing 1 to 3 carbon atoms, such that,together with the atoms to which they are attached, they form a 5 or 6membered ring, R₃ is a) H, b) an aryl or heteroaryl group optionallysubstituted by one or more substituents selected from i) halo, ii) analkyl group containing 1 to 3 carbon atoms optionally substituted by oneor more halo, iii) an alkoxy group containing 1 to 3 carbon atomsoptionally substituted by one or more halo, iv) an alkylthio groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, c) an arylmethyl group in which the aryl is optionally substitutedby one or more substituents selected from i) halo, ii) an alkyl groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, iii) an alkoxy group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, iv) an alkylthio group containing 1 to3 carbon atoms optionally substituted by one or more halo; or d) analkoxyalkyl group containing 3 to 6 carbon atoms; and R₄ and R₅, whichmay be the same or different, independently are an alkyl groupcontaining 1 to 3 carbon atoms, or R₄ and R₅ together with the atom towhich they are attached form a cycloalkyl ring containing 3 to 6 carbonatoms.
 2. Compounds as claimed in claim 1 in which Ar is naphthyl,benzo[b]thiophenyl or phenyl optionally substituted by one or moresubstituents selected from halo, an alkylthio group containing 1 to 3carbon atoms, or a phenoxy group.
 3. Compounds as claimed in claim 1 inwhich R₁ and R₂, which may be the same or different, independently area) an alkyl group containing 1 to 4 carbon atoms, b) an alkenyl groupcontaining 3 or 4 carbon atoms, c) a cycloalkyl group containing 3 to 5carbon atoms, d) a cycloalkylmethyl group in which the ring contains 3to 5 carbon atoms, e) an aryl or heteroaryl group optionally substitutedby one or more substituents selected from i) halo, ii) an alkyl groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, iii) an alkoxy group containing 1 to 3 carbon atoms, f) anarylalkyl or heteroarylalkyl group in which the alkyl chain contains 1or 2 carbon atoms and in which the aryl or heteroaryl group mayoptionally be substituted by one or more substituents selected from haloor an alkoxy group containing 1 to 3 carbon atoms; or R₁ and R₂ form analkylene chain such that, together with the atoms to which they areattached, they form a 5 or 6 membered ring, optionally substituted byone or more methyl groups.
 4. Compounds as claimed in claim 1 in whichR₃ is H, an aryl or heteroaryl group optionally substituted by one ormore halo, an arylmethyl group in which the aryl is optionallysubstituted by one or more halo, or an alkoxyalkyl group containing 3 to6 carbon atoms.
 5. Compounds as claimed in claim 1 in which R₄ and R₅,which may be the same or different, independently are methyl, or R₄ andR₅ together with the atom to which they are attached form a cycloalkylring containing 3 to 6 carbon atoms.
 6. Compounds as claimed in claim 1in which R₁ and R₂ are identical.
 7. Compounds as claimed in claim 1 inwhich R₁ and R₂ form an alkylene chain such that, together with atoms towhich they are attached, they form a 5 or 6 membered ring, optionallysubstituted by a methyl group.
 8. Compounds as claimed in claim 1 inwhich R₄ and R₅ are identical.
 9. Compounds as claimed in claim 1 inwhich R₄ and R₅ together with the atom to which they are attached form acyclobutane, cyclopentane or cyclohexane ring.
 10. Compounds as claimedin claim 1 as represented by Formula Ia

including pharmaceutically acceptable salts thereof in the form ofindividual enantomers, racemates, or other mixtures of enantiomers, inwhich m is2, 3 or 4; n is2 or 3; Ar is phenyl or naphthyl, each of whichmay be optionally substituted by one or more substituents selected froma) halo, b) an alkyl group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, c) an alkoxy group containing 1 to 3carbon atoms optionally substituted by one or more halo, d) an alkylthiogroup containing 1 to 3 carbon atoms optionally substituted by one ormore halo, or e) phenyl; R_(a) and R_(b) independently are H or an alkylgroup containing 1 to 3 carbon atoms optionally substituted by one ormore halo; and R₃ is H.
 11. A compound selected from3-[1-(3,4-Dichlorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;3-[1-(4-Chlorophenyl)cyclobutyl]-6,7-dihydro-5H-thiazolo[3,2-a]pyrmidine;3-[1-(4-Chlorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;3-[1-(3,4-Dichlorophenyl)cyclobutyl)-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine;3-[1-(2-Naphthyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;3-[1-(3,4-Dichlorophenyl)cyclopentyl]-5,6-dihydroimidazo[2,1-b]thiazole;2-Benzyl-3-[1-(4-chlorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;3-[1-(3,4-Dichlorophenyl)cyclobutyl]-2-(2-methoxyethyl)-5,6-dihydroimidazo[2,1-b]thiazole;3-[1-(3,4-Dichlorophenyl)cyclobutyl]-2-phenyl-5,6-dihydroimidazo[2,1-b]thiazole;2-(4-Chlorophenyl)-3-[1-(3,4-dichlorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;3-[1-(3,4-Dichlorophenyl)-1-methylethyl]-5,6-dihydroimidazo[2,1-b]thiazole;3-[1-(Benzo[b]thiophen-2-yl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;3-[1-(3,4-Dichlorophenyl)cyclobutyl]-5-methyl-5,6-dihydroimidazo[2,1-b]-thiazole;3-[1-(3,4-Dichlorophenyl)cyclobutyl]-6-methyl-5,6-dihydroimidazo[2,1-b]-thiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-methyl-2-methylimino-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-ethyl-2-ethylimino-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-propyl-2-propylimino-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-isopropyl-2-isopropylimino-2,3-dihydrothiazole;3-Butyl-2-butylimino-4-[1-(3,4-dichlorophenyl)cyclobutyl]-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-isobutyl-2-isobutylimino-2,3dihydrothiazole;3-Allyl-2-allylimino-4-[1-(3,4-dichlorophenyl)cyclobutyl]-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-cyclopropylmethyl-2-cyclopropylmethylimino]-2,3-dihydrothiazole;3-Benzyl-2-benzylimino-4-[1-(3,4-dichlorophenyl)cyclobutyl]-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobuty]-3-(4-fluorobenzyl)-2-(4-fluorobenzylimino)-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-phenethyl-2-phenethylimino-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(3-pyridylmethyl)-2-(3-pyridyimethylimino)-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-furfuryl-2-furfurylimino-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-phenyl-2-phenylimino-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(p-tolyl)-2-(p-tolylimino)-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(o-tolyl)-2-(o-tolylimino)-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(3-trifluoromethylphenyl)-2-(3-trifluoromethylphenylimino)-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(2,4-xylyl)-2-(2,4-xylylimino)-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(4-ethoxypheny-2-(4-ethoxyphenylimino)-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)cyclobutyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazole;3-[1-(2-Naphthyl)cyclobutyl]-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine;5-Methyl-3-[1-(2-naphthyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;6-Methyl-3-[1-(2-naphthyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;3-Methyl-2-methylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;3-Ethyl-2-ethylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;4-[1-(2-Naphthyl)cyclobutyl]-3-propyl-2-propylimino-2,3-dihydrothiazole;3-Isopropyl-2-isopropylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;3-Butyl-2-butylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;3-Isobutyl-2-isobutylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;3-Allyl-2-allylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;3-Cyclopropylmethyl-2-cyclopropylmethylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;3-Benzyl-2-benzylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;3-(4-Fluorobenzyl)-2-(4-fluorobenzylimino)-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;4-[1-(2-Naphthyl)cyclobutyl]-3-phenethyl-2-phenethylimino-2,3-dihydrothiazolehydrobromide;4-[1-(2-Naphthyl)cyclobutyl]-3-(3-pyridylmethyl)-2-(3-pyridylmethylimino)-2,3-dihydrothiazole;3-Furfuryl-2-furfurylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;4-[1-(2-Naphthyl)cyclobutyl]-3-phenyl-2-phenylimino-2,3-dihydrothiazole;4-[1-(2-Naphthyl)cyclobutyl]-3-(p-tolyl)-2-(p-tolylimino)-2,3-dihydrothiazole;4-[1-(2-Naphthyl)cyclobutyl]-3-(o-tolyl)-2-(o-tolylimino)-2,3-dihydrothiazole;4-[1-(2-Naphthyl)cyclobutyl]-3-(2,4-xylyl)-2-(2,4-xylylimino)-2,3-dihydrothiazole;3-Cyclopentyl-2-cyclopentylimino-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;3-(4-Ethoxyphenyl)-2-(4-ethoxyphenylimino)-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;3-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-4-[1-(2-naphthyl)cyclobutyl]-2,3-dihydrothiazole;3-Butyl-2-butylimino-4-[1-(4-chlorophenyl)cyclobutyl]-2,3-dihydrothiazole;4-[1-(4-Bromophenyl)cyclobutyl]-3-butyl-2-butylimino-2,3-dihydrothiazole;3-Butyl-2-butylimino-4-[1-(4-methylthiophenyl)cyclobutyl]-2,3-dihydrothiazole;3-Butyl-2-butylimino-4-[1-(4-phenoxyphenyl)cyclobutyl]-2,3-dihydrothiazole;3-Butyl-2-butylimino-4-[1-(4-chlorophenyl)cyclopentyl]-2,3-dihydrothiazole;3-Butyl-2-butylimino-4-(1-phenylcyclohexyl)-2,3-dihydrothiazole;3-Butyl-2-butylimino-4-[1-(4-chlorophenyl)-1-methylethyl]-2,3-dihydrothiazole;3-Butyl-2-butylimino-4-[1-(3,4-dichlorophenyl)-1-methylethyl]-2,3-dihydrothiazole;4-[1-(4-Chlorophenyl)cyclobutyl]-3-phenethyl-2-phenethylimino-2,3-dihydrothiazole;4-[1-(4-Chlorophenyl)cyclobutyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazole;4-[1-(4-Bromophenyl)cyclobutyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazole;4-[1-(4-Chlorophenyl)cyclopentyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazole;3-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-4-(1-phenylcyclohexyl)-2,3-dihydrothiazole;4-[1-(3,4-Dichlorophenyl)-1-methylethyl]-3-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenethylimino)-2,3-dihydrothiazole;3-[1-(4-Bromophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;3-[1-(4-Chlorophenyl)cyclopentyl]-5,6-dihydroimidazo[2,1-b]thiazole;3-(1-Phenylcyclohexyl)-5,6-dihydroimidazo[2,1-b]thiazole;3-[1-(4-Chlorophenyl)-1-methylethyl]-5,6-dihydroimidazo[2,1-b]thiazole;3-[1-(3,4-Dichlorophenyl)-1-methylethyl]-5,6-dihydroimidazo[2,1-b]thiazole;3-[1-(3-Fluorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole; and3-[1-(4-Methylthiophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole;and pharmaceutically acceptable salts thereof.
 12. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula I, as claimed in claim 1, together with a pharmaceuticallyacceptable diluent or carrier.
 13. A method of treating depression,anxiety, Parkinson's disease, obesity, cognitive disorders, seizures,and of neuroprotection to protect against stroke in human beings,comprising the administration of a therapeutically effective amount of acompound of Formula I, as claimed in claim 1, to a patient in needthereof.
 14. A process for the preparation of compounds of Formula I, asclaimed in claim 1, comprising heating a compound of Formula II

in which Ar, R₁, R₂, R₃, R₄ and R₅ are as defined for Formula I in claim1, optionally in the presence of an acid.
 15. The compounds of claim 2,wherein Ar is 2-naphthyl, benzo(b)thiophen-2-yl, 4-chlorophenyl,3-4-dichlorophenyl, 4-bromophenyl or 4-methylthiophenyl.
 16. Thecompounds of claim 1, wherein R₁ and R₂ are a) an alkyl group containing1 to 4 carbon atoms, b) allyl, c) cyclopentyl, d) cyclopropylmethyl, e)an aryl group optionally substituted by one or more substituentsselected from i) halo, ii) methyl, iii) trifluoromethyl, iv) ethoxy, f)an arylalkyl or heteroarylalkyl group in which the alkyl chain contains1 or 2 carbon atoms and in which the aryl or heteroaryl group mayoptionally be substituted by one or more substituents selected from haloor methoxy; or R₁ and R₂ form an alkylene chain such that, together withthe atoms to which they are attached, they form a 5 or 6 membered ring,optionally substituted by one or more methyl groups.
 17. The compoundsof claim 16, wherein R₁ and R₂ are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, allyl, cyclopropylmethyl, benzyl, 4-fluorobenzyl,pyrid-3-ylmethyl, furfuryl, phenethyl or 2-(3,4-dimethyloxyphenyl)ethyl;or R₁ and R₂ form an alkylene chain such that, together with the atomsto which they are attached, they form a 5 or 6 membered ring, optionallysubstituted by a methyl group.
 18. The compounds of claim 17, wherein R₁and R₂ are identical.
 19. The compounds of claim 1, wherein R₃ is H, anaryl or heteroaryl group optionally substituted by one or more halo, anarylmethyl group in which the aryl is optionally substituted by one ormore halo, or an alkoxyalkyl group containing 3 to 6 carbon atoms. 20.The compounds of claim 19, wherein R₃ is H, phenyl, 4-chlorophenyl,benzyl or 2-methoxyethyl.
 21. The compounds of claim 20, wherein R₃ isH.
 22. The compounds of claim 10, wherein m is 3, n is 2 or 3, Ar isphenyl or naphthyl, each of which may be optionally substituted by oneor more substituents selected from a) halo, b) an alkyl group containing1 to 3 carbon atoms optionally substituted by one or more halo, c) analkoxy group containing 1 to 3 carbon atoms optionally substituted byone or more halo, d) an alkylthio group containing 1 to 3 carbon atomsoptionally substituted by one or more halo, or e) phenyl, R_(a) andR_(b) independently are H or an alkyl group containing 1 to 3 carbonatoms optionally substituted by one or more halo and R₃ is H.
 23. Thecompounds of claim 22, wherein n is
 2. 24. The compounds of claim 10,wherein R_(a), R_(b) and R₃ are each H.
 25. The compounds of claim 22,wherein R_(a), R_(b) and R₃ are each H. 26.3-(1-(2-naphthyl)cyclobutyl)-5,6-dihydroimidazo(2,1-b)thiazole andpharmaceutically acceptable salts thereof.